Methods of cancer treatment using naaladase inhibitors

ABSTRACT

The present disclosure relates to dipeptidase inhibitors, and more particularly, to novel methods of using phosphonate derivatives, hydroxyphosphinyl derivatives, and phosphoramidate derivatives to inhibit N-Acetylated α-Linked Acidic Dipeptidase (NAALADase) enzyme activity, and to treat prostate diseases, especially using the compounds of the present invention for the inhibition of the growth of prostate cancer cells.

RELATED APPLICATIONS

[0001] This application is a continuation-in-part (CIP) of U.S. patentapplication Ser. No. 08/665,775, filed Jun. 17, 1996, entitled “Methodsof Cancer Treatment Using NAALADase Inhibitors”.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates to novel methods of treatingcancer, preventing tumor cell growth, inhibiting prostate tumor cellgrowth, and inhibiting NAALADase enzyme activity, by administering aneffective amount of a NAALADase inhibitor.

[0004] 2. Description of the Prior Art

Prostate Cancer

[0005] Prostate cancer is the leading form of cancer and the secondleading cause of death from cancer for men in the United States. TheAmerican Cancer Society has estimated that in 1996 alone, 317,100 newcases of prostate cancer were diagnosed and 41,400 deaths were caused byprostate cancer. The incidence rate of prostate cancer increased 65%between 1980 and 1990, and will continue to rise with improved screeningtests and longer life expectancies. While most men used to die of otherillnesses before prostate cancer had a chance to develop, higherprostate cancer mortality rates are expected as men live longer and thedisease has more time to progress.

[0006] In 1993, the molecular cloning of Prostate Specific MembraneAntigen (PSMA) was reported as a potential prostate carcinoma marker andhypothesized to serve as a target for imaging and cytotoxic treatmentmodalities for prostate cancer. PSMA antibodies, particularly indium-111labelled and tritium labelled PSMA antibodies, have been described andexamined clinically for the diagnosis and treatment of prostate cancer.PSMA is expressed in prostatic ductal epithelium and is present inseminal plasma, prostatic fluid and urine. In 1996, it was found thatthe expression of PSMA cDNA confers the activity of NAALADase.

NAALADase Inhibitors

[0007] NAAG and NAALADase have been implicated in several human andanimal pathological conditions relating to glutamate abnormalities andneurotoxicity. For example, it has been demonstrated thatintra-hippocampal injections of NAAG elicit prolonged seizure activity.More recently, it was reported that rats genetically prone to epilepticseizures have a persistent increase in their basal level of NAALADaseactivity. These observations lend support the hypothesis that increasedavailability of synaptic glutamate elevates seizure susceptibility, andsuggest that NAALADase inhibitors may provide anti-epileptic activity.

[0008] NAAG and NAALADase have also been implicated in the pathogenesisof ALS and in the pathologically similar animal disease calledHereditary Canine Spinal Muscular Atrophy (HCSMA). It has been shownthat concentrations of NAAG and its metabolites—NAA, glutamate andaspartate—are elevated two- to three-fold in the cerebrospinal fluid ofALS patients and HCSMA dogs. Additionally, NAALADase activity issignificantly increased (two- to three-fold) in post-mortem spinal cordtissue from ALS patients and HCSMA dogs. As such, NAALADase inhibitorsmight be clinically useful in curbing the progression of ALS if anincreased metabolism of NAAG is responsible for the alterations of CSFlevels of these acidic amino acids and peptides.

[0009] Abnormalities in NAAG levels and NAALADase activity have alsobeen documented in post-mortem schizophrenic brain, specifically in theprefrontal and limbic brain regions.

[0010] The findings described above suggest that NAALADase inhibitorscould be useful in treating glutamate abnormalities. However, thepresent invention is directed to the surprising and unexpected discoverythat the novel compounds of the present invention are not only effectiveNAALADase inhibitors but are effective in treating prostate diseases,particularly prostate cancer. Although the cancer data relate toprostate cancer cells, NAALADase inhibitors are expected to be equallyeffective in treating cancer of other tissues where NAALADase enzymereside, such as the brain, kidney and testis.

[0011] While a few NAALADase inhibitors have been identified, they haveonly been used in non-clinical research. Examples of such inhibitorsinclude general metallopeptidase inhibitors such as o-phenanthroline,metal chelators such as EGTA and EDTA, and peptide analogs such asquisqualic acid and β-NAAG. Accordingly, a need exists for moreNAALADase inhibitors to be identified and, particularly, for thetreatment of prostate diseases such as prostate cancer.

SUMMARY OF THE INVENTION

[0012] The present invention is directed to novel methods for treatingcancer, preventing tumor cell growth, inhibiting prostate tumor cellgrowth, and inhibiting NAALADase enzyme activity, in an animal,comprising administering an effective amount of a NAALADase inhibitor.

[0013] Preferred NAALADase inhibitors include compounds of formula I:

[0014] wherein

[0015] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁;

[0016] X is CH₂, O, or N; and

[0017] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or arylgroups may be optionally substituted with carboxylic acid.

[0018] Preferably, the compound of formula I is present in an amountthat is effective for inhibiting NAALADase enzyme activity, or treatinga prostate disease in an animal.

[0019] The present invention further relates to a method of inhibitingNAALADase enzyme activity in an animal, comprising administering aneffective amount of the compound of formula I to said animal.

BRIEF DESCRIPTION OF THE FIGURES

[0020]FIG. 1 is a bar graph plotting the growth of the prostate cancercell line, LNCAP, against various concentrations of quisqualic acid, aNAALADase Inhibitor. FIG. 1 shows the effect of 7-day treatment withquisqualate on the growth of LNCAP cells. Concentrations ranging from 10nM to 1 μM of quisqualate show a sharp dose-dependent decrease of LNCAPcell proliferation as indicated by the significant decrease in theincorporation of [3H]thymidine.

[0021]FIG. 2 is a bar graph plotting the growth of the prostate cancercell line, LNCAP, against various concentrations of2-(phosphonomethyl)pentanedioic acid, a NAALADase Inhibitor. FIG. 2shows the effect of 7-day treatment with 2-(phosphonomethyl)pentanedioicacid on the growth of LNCAP cells. Concentrations ranging from 100 pM to10 nM of 2-(phosphonomethyl)pentanedioic acid show a sharpdose-dependent decrease of LNCAP cell proliferation as indicated by thesignificant decrease in the incorporation of [3H]thymidine.

[0022]FIG. 3 is a line graph of the response of LNCAP human prostatetumors to daily treatment with 2-(phosphonomethyl)pentanedioic acid.Mean of individual tumor volumes are plotted as a function of time afterthe start of treatment. Error bars represent the SEM. Treatment with2-(phosphonomethyl)pentanedioic acid for six weeks resulted instatistically significant difference between both the control group andanimals given daily injections of drug (p=0.04), and the control groupand animals implanted with polymer (p=0.02).

[0023]FIG. 4 is a line graph plotting the survival percentage of animalstreated with injections against the number of days. FIG. 4 shows thehigher mean survival percentage of animals injected with2-(phosphonomethyl)pentanedioic acid mixed with polymer as compared tothose animals only receiving intratumoral injections of2-(phosphonomethyl)pentanedioic acid or a vehicle control. The graphshows that 88% of the animals treated with polymer were alive after 72days, and those animals had small tumors.

[0024]FIG. 5 is a line graph plotting tumor growth against daysfollowing rat dunning cell injections. Cells were injected, over aperiod of 84 days, with various dosages of2-(phosphonomethyl)pentanedioic acid and a control vehicle. FIG. 5 showsthat tumor growth slowed as a function of2-(phosphonomethyl)pentanedioic acid dosage.

[0025]FIG. 6 is a line graph of the response of R3327 rat prostatetumors to daily treatment with2-[[(phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid. Mean ofindividual tumor volumes expressed relative to the volume at the startof treatment (V/V_(o)) are plotted as a function of time. Treatment with2-[[(phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid for 2.5weeks resulted in a statistically significant difference between thecontrol group and animals given daily injections of 1 μg of drug(p=0.02).

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0026] “Compound 3” refers to 2-(phosphonomethyl)pentanedioic acid, aNAALADase inhibitor.

[0027] “Inhibition”, in the context of enzymes, refers to reversibleenzyme inhibition such as competitive, uncompetitive and non-competitiveinhibition. Competitive, uncompetitive and non-competitive inhibitioncan be distinguished by the effects of an inhibitor on the reactionkinetics of an enzyme. Competitive inhibition occurs when the inhibitorcombines reversibly with the enzyme in such a way that it competes witha normal substrate for binding at the active site. The affinity betweenthe inhibitor and the enzyme may be measured by the inhibitor constant,K_(i), which is defined as:$K_{i} = \frac{\lbrack E\rbrack \lbrack I\rbrack}{\lbrack{EI}\rbrack}$

[0028] wherein [E] is the concentration of the enzyme, [I] is theconcentration of the inhibitor, and [EI] is the concentration of theenzyme-inhibitor complex formed by the reaction of the enzyme with theinhibitor. Unless otherwise specified, K_(i) as used herein refers tothe affinity between the inventive compounds and NAALADase. “IC50” is arelated term used to define the concentration or amount of a compoundwhich is required to cause a 50% inhibition of the target enzyme.

[0029] The term “inhibition”, in the context of tumor growth or tumorcell growth, may be assessed by delayed appearance of primary orsecondary tumors, slowed development of primary or secondary tumors,decreased occurrence of primary or secondary tumors, slowed or decreasedseverity of secondary effects of disease, arrested tumor growth andregression of tumors, among others. In the extreme, complete inhibition,is referred to herein as prevention.

[0030] “NAAG” refers to N-acetyl-aspartyl-glutamate, an importantpeptide component of the brain, with levels comparable to the majorinhibitor neurotransmitter gamma-aminobutyric acid (GABA). NAAG isneuron-specific, present in synaptic vesicles and released upon neuronalstimulation in several systems presumed to be glutamatergic. Studiessuggest that NAAG may function as a neurotransmitter and/orneuromodulator in the central nervous system, or as a precursor of theneurotransmitter glutamate.

[0031] “NAALADase” refers to N-acetylated α-linked acidic dipeptidase, amembrane-bound metallopeptidase which catabolizes NAAG toN-acetylaspartate (NAA) and glutamate:

Catabolism of NAAG by NAALADase

[0032]

[0033] NAALADase shows a high affinity for NAAG with a Km of 540 nM. IfNAAG is a bioactive peptide, then NAALADase may serve to inactivateNAAGIS synaptic action. Alternatively, if NAAG functions as a precursorfor glutamate, the primary function of NAALADase may be to regulatesynaptic glutamate availability.

[0034] “Pharmaceutically acceptable salt” refers to a salt of theinventive compounds which possesses the desired pharmacological activityand which is neither biologically nor otherwise undesirable. The saltcan be formed with inorganic is acids such as acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate heptanoate, hexanoate, hydrochloridehydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,thiocyanate, tosylate and undecanoate. Examples of a base salt includeammonium salts, alkali metal salts such as sodium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine andlysine. The basic nitrogen-containing groups can be quarternized withagents including lower alkyl halides such as methyl, ethyl, propyl andbutyl chlorides, bromides and iodides; dialkyl sulfates such asdimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;and aralkyl halides such as benzyl and phenethyl bromides.

[0035] The term “prevention”, in relation to tumor growth or tumor cellgrowth, means no tumor or tumor cell growth if none had occurred, nofurther tumor or tumor cell growth if there had already been growth.

[0036] The term “prostate disease” relates to prostate cancer such asadenocarcinoma or metastatic cancers, conditions characterized byabnormal growth of prostatic epithelial cells such as benign prostatichyperplasia, and other conditions requiring treatment by the compoundsof the present invention.

[0037] “PSA” refers to Prostate Specific Antigen, a well known prostatecancer marker. It is a protein produced by prostate cells and isfrequently present at elevated levels in the blood of men with prostatecancer. PSA correlates with tumor burden, serves as an indicator ofmetastatic involvement, and provides a parameter for following aprostate cancer patient's response to surgery, irradiation and androgenreplacement therapy.

[0038] “PSMA” refers to Prostate Specific Membrane Antigen, a potentialprostate carcinoma marker that has been hypothesized to serve as atarget for imaging and cytotoxic treatment modalities for prostatecancer. PSMA is expressed in prostatic ductal epithelium and is presentin seminal plasma, prostatic fluid and urine. It has been found that theexpression of PSMA cDNA confers the activity of NAALADase.

[0039] The term “treatment” refers to any process, action, application,therapy, or the like, wherein an animal, including a human being, issubject to medical aid with the object of improving the animal'scondition, directly or indirectly.

Preferred NAALADase Inhibitors of the Present Invention

[0040] The present invention relates to a compound of formula I:

[0041] or a pharmaceutically acceptable salt, hydrate, or a mixturethereof, wherein:

[0042] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁;

[0043] X is CH₂, O, or NR₁, where R₁ is defined above; and

[0044] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid.

[0045] The present invention also contemplates that said alkyl, alkenyl,cycloalkyl, cycloalkenyl or aryl groups may be optionally substitutedwith C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, C₁-C₄alkyl, C₁-C₄ alkenyl, halo, hydroxy, carboxy, nitro, trifluoromethyl,C₁-C₆ straight or branched chain alkyl or alkenyl, C₁-C₄ alkoxy, C₁-C₄alkenyloxy, phenoxy, benzyloxy, amino, or Ar₁, and where Ar₁ is selectedfrom the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 4-indolyl, 2-furyl, 3-furyl, tetrahydrofuranyl, 2-thienyl,3-thienyl, 4-thienyl, 2-, 3-, or 4-pyridyl, or phenyl, having one tofive substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxy, carboxy, nitro, trifluoromethyl,C₁-C₆ straight or branched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄alkenyloxy, phenoxy, benzyloxy, and amino; or pharmaceuticallyacceptable salts, hydrates, or mixtures thereof.

[0046] In a preferred embodiment, the compound is selected from thegroup of formula II:

[0047] wherein

[0048] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; and

[0049] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid.

[0050] In another preferred embodiment, the R groups are either straightor branched aliphatic substituents or carbocyclic substituentsillustrated by the compounds selected from the group of formula II:

[0051] wherein

[0052] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, 1-naphthyl, 2-naphthyl, or phenyl; and

[0053] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl,1-naphthyl, 2-naphthyl, or phenyl, wherein said alkyl, alkenyl,cycloalkyl, cycloalkenyl, 1-naphthyl, 2-naphthyl, or phenyl group may beoptionally substituted with carboxylic acid.

[0054] Especially preferred methods utilize compounds wherein R₁ iseither a straight or branched aliphatic group or a carbocyclic group, R₂is ethyl which is substituted with a carboxylic acid, and X is CH₂ areselected from the group consisting of:

[0055] 2-[[methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0056] 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;

[0057] 2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;

[0058] 2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;

[0059] 2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;

[0060] 2-[[(cyclohexyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0061] 2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;

[0062] 2-[[benzylhydroxyphosphinyl]methyl]pentanedioic acid;

[0063] 2-[[phenylethylhydroxyphosphinyl]methyl]pentanedioic acid;

[0064] 2-[[phenylpropylhydroxyphosphinyl]methyl]pentanedioic acid;

[0065] 2-[[phenylbutylhydroxyphosphinyl]methyl]pentanedioic acid;

[0066] 2-[[(4methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0067] 2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0068] 2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0069] 2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioicacid;

[0070] 2-[[(methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0071] 2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0072] 2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioicacid;

[0073] 2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0074] 2-(phosphonomethyl)pentanedioic acid;

[0075] 2[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl]pentanedioicacid;

[0076] 2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]methyl]pentanedioicacid;

[0077] 2-[[(1-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0078] 2-[[(2-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0079] 2-[[(1-naphthyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0080] 2-[[(2-naphthyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0081] 2-[[(1-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

[0082] 2-[[(2-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

[0083] 2-[[(1-naphthyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

[0084] 2-[[(2-naphthyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

[0085] 2-[[(1-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;

[0086] 2-[[(2-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;and

[0087] 2-[[(phenylprop-2-enyl)hydroxyphosphinyl]methyl]pentanedioicacid.

[0088] Especially preferred methods utilize compounds wherein R₁ iseither a straight or branched aliphatic group or a carbocyclic group, R₂is ethyl which is substituted with a carboxylic acid, and X is CH₂ areselected from the group consisting of:

[0089] 2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid;

[0090] 2-[(phenylhydroxyphosphinyl)methyl]pentanedioic acid;

[0091] 2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioicacid;

[0092] 2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid;

[0093] 2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0094] 2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid;

[0095] 2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0096] 2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid;

[0097] 2-[(phenylethylhydroxyphosphinyl)methyl]pentanedioic acid;

[0098] 2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0099] 2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0100] 2-[[(4-methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0101] 2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0102] 2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioicacid;

[0103] 2-(phosphonomethyl)pentanedioic acid; and

[0104]2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid.

[0105] Especially preferred methods utilize compounds wherein R₁ is astraight or branched aliphatic group or a carbocyclic group, R₂ isphenyl, and X is CH₂ are selected from the group consisting of:

[0106] 3-(methylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0107] 3-(ethylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0108] 3-(propylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0109] 3-(butylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0110] 3-(cyclohexylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0111] 3-((cyclohexyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0112] 3-(phenylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0113] 3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0114] 3-(phenylethylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0115] 3-(phenylpropylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0116] 3-(phenylbutylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0117]3-[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]-2-phenylpropanoic acid;

[0118] 3-[(1-naphthyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0119] 3-[(2-naphthyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0120] 3-[(1-naphthyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0121] 3-[(2-naphthyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0122] 3-[(1-naphthyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0123] 3-[(2-naphthyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0124] 3-[(1-naphthyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0125] 3-[(2-naphthyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0126] 3-[(-naphthyl)butyhydroxyphosphinyl]-2-phenylpropanoic acid;

[0127] 3-[(2-naphthyl)butylhydroxyphosphinyl]-2-phenylpropanoic acid;and

[0128] 3-[phenylprop-2-enylhydroxyphosphinyl]-2-phenylpropanoic acid.

[0129] Although not limited to any one species, a highly preferredspecies where R₁ is a straight or branched aliphatic group or acarbocyclic group, R₂ is ethyl which is substituted with carboxylicacid, and X is CH₂ is 2-[[benzylhydroxyphosphinyl]methyl]pentanedioicacid.

[0130] Other preferred compounds of the present invention are selectedfrom the group consisting of: hydroxyphosphinyl derivatives wherein X isCH₂, R₁ is a straight or branched aliphatic group or a carbocyclicgroup, and R₂ is an C₂-C₈ alkyl or alkenyl chain which is substitutedwith a carboxylic acid. Exemplary species include:

[0131] 2-[(methylhydroxyphosphinyl)methyl]hexanedioic acid;

[0132] 2-[(benzylhydroxyphosphinyl)methyl]hexanedioic acid;

[0133] 2-[(methylhydroxyphosphinyl)methyl]heptanedioic acid;

[0134] 2-[(benzylhydroxyphosphinyl)methyl]heptanedioic acid;

[0135] 2-[(methylhydroxyphosphinyl)methyl]octanedioic acid;

[0136] 2-[(benzylhydroxyphosphinyl)methyl]octanedioic acid;

[0137] 2-[(methylhydroxyphosphinyl)methyl]nonanedicic acid;

[0138] 2-[(benzylhydroxyphosphinyl)methyl]nonanedioic acid;

[0139] 2-[(methylhydroxyphosphinyl)methyl]decanedioic acid; and

[0140] 2-[(benzylhydroxyphosphinyl)methyl]decanedioic acid.

[0141] Other preferred compounds are selected from the group consistingof: hydroxyphosphinyl derivatives wherein X is CH₂, R₁ is benzyl, and R₂is a straight or branched aliphatic group or a carbocyclic group.Exemplary species include:

[0142] 3-(benzylhydroxyphosphinyl)-2-methylpropanoic acid;

[0143] 3-(benzylhydroxyphosphinyl)-2-ethylpropanoic acid;

[0144] 3-(benzylhydroxyphosphinyl)-2-propylpropanoic acid;

[0145] 3-(benzylhydroxyphosphinyl)-2-butylpropanoic acid;

[0146] 3-(benzylhydroxyphosphinyl)-2-cyclohexylpropanoic acid;

[0147] 3-(benzylhydroxyphosphinyl)-2-(cyclohexyl)methylpropanoic acid;

[0148] 3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;

[0149] 3-(benzylhydroxyphosphinyl)-2-benzylpropanoic acid;

[0150] 3-(benzylhydroxyphosphinyl)-2-phenylethylpropanoic acid;

[0151] 3-(benzylhydroxyphosphinyl)-2-phenylpropylpropanoic acid;

[0152] 3-(benzylhydroxyphosphinyl)-2-phenylbutylpropanoic acid;

[0153] 3-(benzylhydroxyphosphinyl)-2-(2,3,4-trimethoxyphenyl)propanoicacid;

[0154] 3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propanoic acid;

[0155] 3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propanoic acid;

[0156] 3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)methylpropanoic acid;

[0157] 3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)methylpropanoic acid;

[0158] 3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)ethylpropanoic acid;

[0159] 3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)ethylpropanoic acid;

[0160] 3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propylpropanoic acid;

[0161] 3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propylpropanoic acid;

[0162] 3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)butylpropanoic acid;

[0163] 3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)butylpropanoic acid;and

[0164] 3-(benzylhydroxyphosphinyl)-2-phenylprop-2-enylpropanoic acid.

[0165] Especially preferred methods use compounds wherein R₁ is saidalkyl, alkenyl, cycloalkyl, or aryl group which is substituted with aheterocyclic group, R₂ is ethyl which is substituted with a carboxylicacid, and X is CH₂ are selected from the group consisting of:

[0166] 2-[[(2-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0167] 2-[[(3-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0168] 2-[[(4-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0169] 2-[[(3-pyridyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

[0170] 2-[[(3-pyridyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

[0171]2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0172] 2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]methyl]pentanedioicacid;

[0173]2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

[0174] 2-[[(2-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0175] 2-[[(3-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0176] 2-[[(4-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0177] 2-[[(3-indolyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;

[0178] 2-[[(3-indolyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;

[0179] 2-[[(2-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0180] 2-[[(3-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0181] 2-[[(4-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;

[0182] 2-[[(3-thienyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;and

[0183] 2-[[(3-thienyl)propylhydroxyphosphinyl]methyl]pentanedioic acid.

[0184] Especially preferred methods use compounds wherein R₁ is saidalkyl, alkenyl, cycloalkyl, or aryl group which is substituted with aheterocyclic group, R₂ is phenyl, and X is CH₂ are selected from thegroup consisting of:

[0185] 3-[(2-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0186] 3-[(3-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0187] 3-[(4-pyridyl)methylhydroxyphosphinyl]-2-phenypropanoic acid;

[0188] 3-[(3-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0189] 3-[(3-pyridyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0190] 3-[(tetrahydrofuranyl)methylhydroxyphosphinyl]-2-phenylpropanoicacid;

[0191] 3-[(tetrahydrofuranyl)ethylhydroxyphosphinyl]-2-phenylpropanoicacid;

[0192] 3-[(tetrahydrofuranyl)propylhydroxyphosphinyl]-2-phenylpropanoicacid;

[0193] 3-[(2-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0194] 3-[(3-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0195] 3-[(4-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0196] 3-[(3-indolyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0197] 3-[(3-indolyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0198] 3-[(2-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0199] 3-[(3-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0200] 3-[(4-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;

[0201] 3-[(3-thienyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid; and

[0202] 3-[(3-thienyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid.

[0203] Especially preferred methods use compounds wherein R₁ is benzyl,R₂ is said alkyl, alkenyl, cycloalkyl, or aryl group which issubstituted with a heterocyclic group, and X is CH₂ are selected fromthe group consisting of:

[0204] 3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)methylpropanoic acid;

[0205] 3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)methylpropanoic acid;

[0206] 3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)methylpropanoic acid;

[0207] 3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)methylpropanoic acid;

[0208] 3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propylpropanoic acid;

[0209] 3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)methylpropanoicacid;

[0210] 3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)ethylpropanoicacid;

[0211] 3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propylpropanoicacid;

[0212] 3-(benzylhydroxyphosphinyl)-2-(2-indolyl)methylpropanoic acid;

[0213] 3-(benzylhydroxyphosphinyl)-2-(3-indolyl)methylpropanoic acid;

[0214] 3-(benzylhydroxyphosphinyl)-2-(4-indolyl)methylpropanoic acid;

[0215] 3-(benzylhydroxyphosphinyl)-2-(3-indolyl)methylpropanoic acid;

[0216] 3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propylpropanoic acid;

[0217] 3-(benzylhydroxyphosphinyl)-2-(2-thienyl)methylpropanoic acid;

[0218] 3-(benzylhydroxyphosphinyl)-2-(3-thienyl)methylpropanoic acid;

[0219] 3-(benzylhydroxyphosphinyl)-2-(4-thienyl)methylpropanoic acid;

[0220] 3-(benzylhydroxyphosphinyl)-2-(3-thienyl)ethylpropanoic acid; and

[0221] 3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propylpropanoic acid.

[0222] In another preferred embodiment, the R groups are heterocyclicsubstituents illustrated by the compounds selected from the group havingformula II:

[0223] wherein

[0224] R₁ is Ar₁; and

[0225] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid.

[0226] Especially preferred methods use compounds wherein R₁ is aheterocyclic group, R₂ is ethyl which is substituted with carboxylicacid, and X is CH₂ are selected from the group consisting of:

[0227] 2-[[(2-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0228] 2-[[(3-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0229] 2-[[(4-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0230] 2-[[(tetrahydrofuranyl)hydroxyphosphinyl]methyl]pentanedioicacid;

[0231] 2-[[(2-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0232] 2-[[(3-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0233] 2-[[(4-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0234] 2-[[(2-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;

[0235] 2-[[(3-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid; and

[0236] 2-[[(4-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid.

[0237] Compounds of the present invention wherein R₁ is a heterocyclicgroup, R₂ is phenyl, and X is CH₂ are selected from the group consistingof:

[0238] 3-[(2-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0239] 3-[(3-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0240] 3-[(4-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0241] 3-[(tetrahydrofuranyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0242] 3-[(2-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0243] 3-[(3-indolyl)hydroxyphosphinyl-2-phenylpropanoic acid;

[0244] 3-[(4-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0245] 3-[(2-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;

[0246] 3-[(3-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid; and

[0247] 3-[(4-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid.

[0248] Compounds are also preferably selected from the group of formulaII:

[0249] wherein

[0250] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; and

[0251] R₂ is Ar₁, wherein said aryl group may be optionally substitutedwith carboxylic acid.

[0252] Particular species wherein R₂ is heterocyclic may be easily madeand used by persons of ordinary skill in the art in accordance with theteachings provided herein and known in the art.

[0253] Compounds wherein R₁ is benzyl, R₂ is heterocyclic, and X is CH₂are selected from the group consisting of:

[0254] 3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)propanoic acid;

[0255] 3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propanoic acid;

[0256] 3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)propanoic acid;

[0257] 3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propanoic acid;

[0258] 3-(benzylhydroxyphosphinyl)-2-(2-indolyl)propanoic acid;

[0259] 3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propanoic acid;

[0260] 3-(benzylhydroxyphosphinyl)-2-(4-indolyl)propanoic acid;

[0261] 3-(benzylhydroxyphosphinyl)-2-(2-thienyl)propanoic acid;

[0262] 3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propanoic acid; and

[0263] 3-(benzylhydroxyphosphinyl)-2-(4-thienyl)propanoic acid.

[0264] Preferred compounds are also selected from formula III:

[0265] wherein

[0266] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; and

[0267] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid.

[0268] In another preferred embodiment, the R groups are straight orbranched or carbocyclic substituents illustrated by the compoundsselected from the group of formula III:

[0269] wherein

[0270] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, 1-naphthyl, 2-naphthyl, or phenyl; and

[0271] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl,1-naphthyl, 2-naphthyl, or phenyl, wherein said alkyl, alkenyl,cycloalkyl, cycloalkenyl, 1-naphthyl, 2-naphthyl, or phenyl group may beoptionally substituted with carboxylic acid.

[0272] Especially preferred compounds of Formula III of the presentinvention wherein R₁ is a straight or branched aliphatic group or acarbocyclic group and R₂ is ethyl which is substituted with a carboxylicacid are selected from the group consisting of:

[0273] 2-[[methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0274] 2-[[ethylhydroxyphosphinyl]oxy]pentanedioic acid;

[0275] 2-[[propylhydroxyphosphinyl]oxy]pentanedioic acid;

[0276] 2-[[butylhydroxyphosphinyl]oxy]pentanedioic acid;

[0277] 2-[[cyclohexylhydroxyphosphinyl]oxy]pentanedioic acid;

[0278] 2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0279] 2-[[phenylhydroxyphosphinyl]oxy]pentanedioic acid;

[0280] 2-[[benzylhydroxyphosphinyl]oxy]pentanedioic acid;

[0281] 2-[[phenylethylhydroxyphosphinyl]oxy]pentanedioic acid;

[0282] 2-[[phenylpropylhydroxyphosphinyl]oxy]pentanedioic acid;

[0283] 2-[[phenylbutylhydroxyphosphinyl]oxy]pentanedioic acid;

[0284] 2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0285] 2-[[(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0286] 2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0287] 2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0288] 2-[[(methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0289] 2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0290] 2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy]pentanedioicacid;

[0291] 2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0292] 2-(phosphono)oxy]pentanedioic acid;

[0293] 2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy]pentanedioicacid;

[0294] 2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]oxy]pentanedioicacid;

[0295] 2-[[(1-naphthyl)hydroxyphosphinyl]oxy]pentanedicic acid;

[0296] 2-[[(2-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0297] 2-[[(1-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0298] 2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0299] 2-[[(1-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

[0300] 2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

[0301] 2-[[(1-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

[0302] 2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

[0303] 2-[[(1-naphthyl)butylhydroxyphosphinyl]oxy]pentanedioic acid;

[0304] 2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]pentanedioic acid; and

[0305] 2-[[(phenylprop-2-enyl)hydroxyphosphinyl]oxy]pentanedioic acid.

[0306] Especially preferred compounds of Formula III of the presentinvention wherein R₁ is a straight or branched aliphatic group or acarbocyclic group and R₂ is ethyl which is substituted with a carboxylicacid are selected from the group consisting of:

[0307] 2-[(benzylhydroxyphosphinyl)oxy]pentanedioic acid;

[0308] 2-[(phenylhydroxyphosphinyl)oxy]pentanedioic acid;

[0309] 2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy]pentanedioicacid;

[0310] 2-[(butylhydroxyphosphinyl)oxy]pentanedioic acid;

[0311] 2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0312] 2-[(3-phenylpropylhydroxyphosphinyl)oxy]pentanedioic acid;

[0313] 2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0314] 2-(methylhydroxyphosphinyl)oxypentanedioic acid;

[0315] 2-[(phenylethylhydroxyphosphinyl)oxy]pentanedioic acid;

[0316] 2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0317] 2-[[(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0318] 2-[[(4-methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0319] 2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0320] 2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0321] 2-[(phosphono)oxy]pentanedioic acid; and

[0322] 2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy]pentanedioicacid.

[0323] Compounds of the present invention wherein R₁ is a straight orbranched aliphatic group or a carbocyclic group, R₂ is phenyl, and X isoxygen are selected from the group consisting of:

[0324] 2-[[methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0325] 2-[[ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0326] 2-[[propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0327] 2-[[butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0328] 2-[[cyclohexylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0329] 2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0330] 2-[[phenylhydroxyphosphinyl]oxy-2-phenylethanoic acid;

[0331] 2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0332] 2-[[phenylethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0333] 2-[[phenylpropylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0334] 2-[[phenylbutylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0335]2-[[(2,3,4-trimnethoxyphenyl)-3-hydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0336] 2-[[(1-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0337] 2-[[(2-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0338] 2-[[(1-naphthyl)methylhydroxyphosphinyl)]oxy]-2-phenylethanoicacid;

[0339] 2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0340] 2-[[(1-naphthyl)ethylhydroxyphosphinyl]oxy]2-phenylethanoic acid;

[0341] 2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy-2-phenylethanoic acid;

[0342] 2-[[(1-naphthyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0343] 2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0344] 2-[[(1-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0345] 2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenylethanoicacid; and

[0346] 2-[[phenylprop-2-enylhydroxyphosphinyl]oxy]-2-phenylethanoicacid.

[0347] Although not limited to any one particular species, a highlypreferred species where R₁ is a straight or branched aliphatic group ora carbocyclic group, R₂ is ethyl which is substituted with carboxylicacid, and X is oxygen is 2-[[benzylhydroxyphosphinyl]oxy]pentanedioicacid.

[0348] Other especially preferred compounds of the present invention areselected from the group consisting of: phosphonate derivatives wherein Xis oxygen, R₁ is a straight or branched aliphatic group or a carbocyclicgroup, and R₂ is an C₂-C₈ alkyl or alkenyl chain which is substitutedwith a carboxylic acid. Exemplary species include:

[0349] 2-[(methylhydroxyphosphinyl)oxy]hexanedioic acid;

[0350] 2-[(benzylhydroxyphosphinyl)oxy]hexanedioic acid;

[0351] 2-[(methylhydroxyphosphinyl)oxy]heptanedioic acid;

[0352] 2-[(benzylhydroxyphosphinyl)oxy]heptanedioic acid;

[0353] 2-[(methylhydroxyphosphinyl)oxy]octanedioic acid;

[0354] 2-[(benzylhydroxyphosphinyl)oxy]octanedioic acid;

[0355] 2-[(methylhydroxyphosphinyl)oxy]nonanedioic acid;

[0356] 2-[(benzylhydroxyphosphinyl)oxy]nonanedioic acid;

[0357] 2-[(methylhydroxyphosphinyl)oxy]decanedioic acid; and

[0358] 2-[(benzylhydroxyphosphinyl)oxy]decanedioic acid.

[0359] Other especially preferred compounds are selected from the groupconsisting of: phosphonate derivatives wherein X is oxygen, R₁ isbenzyl, and R₂ is a straight or branched aliphatic group or acarbocyclic group. Exemplary species include:

[0360] 2-[[benzylhydroxyphosphinyl]oxy]-2-methylethanoic acid;

[0361] 2-[[benzylhydroxyphosphinyl]oxy]-2-ethylethanoic acid;

[0362] 2-[[benzylhydroxyphosphinyl]oxy]-2-propylethanoic acid;

[0363] 2-[[benzylhydroxyphosphinyl]oxy]-2-butylethanoic acid;

[0364] 2-[[benzylhydroxyphosphinyl]oxy]-2-cyclohexylethanoic acid;

[0365] 2-[[benzylhydroxyphosphinyl]oxy]-2-(cyclohexyl)methylethanoicacid;

[0366] 2-[[benzylhydroxyphosphinyl]oxy]-2phenylethanoic acid;

[0367] 2-[[benzylhydroxyphosphinyl]oxy]-2-benzylethanoic acid;

[0368] 2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethylethanoic acid;

[0369] 2-[[benzylhydroxyphosphinyl]oxy]-2-phenylpropylethanoic acid;

[0370] 2-[[benzylhydroxyphosphinyl]oxy]-2-phenylbutylethanoic acid;

[0371]2-[[benzylhydroxyphosphinyl]oxy]-2-(2,3,4-trimethoxyphenyl)ethanoicacid;

[0372] 2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethanoic acid;

[0373] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethanoic acid;

[0374] 2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)methylethanoicacid;

[0375] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)methylethanoicacid;

[0376] 2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethylethanoicacid;

[0377] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethylethanoicacid;

[0378] 2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)propylethanoicacid;

[0379] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)propylethanoicacid;

[0380] 2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)butylethanoicacid;

[0381] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)butylethanoicacid; and

[0382] 2-[[benzylhydroxyphosphinyl]oxy]-2-phenylprop-2-enylethanoicacid.

[0383] Especially preferred methods utilize compounds wherein R₁ is saidalkyl, alkenyl, cycloalkyl, or aryl group which is substituted with aheterocyclic group, R₂ is ethyl which is substituted with a carboxylicacid, and X is oxygen are selected from the group consisting of:

[0384] 2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0385] 2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0386] 2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0387] 2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

[0388] 2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

[0389] 2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]pentanedioicacid;

[0390] 2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]pentanedioicacid;

[0391] 2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]pentanedioicacid;

[0392] 2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0393] 2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0394] 2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0395] 2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;

[0396] 2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;

[0397] 2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0398] 2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0399] 2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;

[0400] 2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid; and

[0401] 2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]pentanedioic acid.

[0402] Especially preferred methods utilize compounds wherein R₁ is saidalkyl, alkenyl, cycloalkyl, or aryl group which is substituted with aheterocyclic group, R₂ is phenyl, and X is oxygen are selected from thegroup consisting of:

[0403] 2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0404] 2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0405] 2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0406] 2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0407] 2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0408]2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0409]2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0410]2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0411] 2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0412] 2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0413] 2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0414] 2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0415] 2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0416] 2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0417] 2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0418] 2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0419] 2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;and

[0420] 2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid.

[0421] Especially preferred methods utilize compounds wherein R₁ isbenzyl, R₂ is said alkyl, alkenyl, cycloalkyl, or aryl group which issubstituted with a heterocyclic group, and X is oxygen are selected fromthe group consisting of:

[0422] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)methylethanoicacid;

[0423] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)methylethanoicacid;

[0424] 2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)methylethanoicacid;

[0425] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethylethanoic acid;

[0426] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)propylethanoicacid;

[0427]2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl)methylethanoicacid;

[0428]2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl)ethylethanoicacid;

[0429]2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl)propylethanoicacid;

[0430] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)methylethanoicacid;

[0431] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)methylethanoicacid;

[0432] 2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)methylethanoicacid;

[0433] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethylethanoic acid;

[0434] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)propylethanoicacid;

[0435] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)methylethanoicacid;

[0436] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)methylethanoicacid;

[0437] 2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)methylethanoicacid;

[0438] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethylethanoic acid;and

[0439] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)propylethanoicacid.

[0440] In another preferred embodiment, R₁ is a heterocyclic substituentillustrated by the compounds selected from the group of formula III:

[0441] wherein

[0442] R₁ is Ar₁; and

[0443] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid.

[0444] Especially preferred compounds wherein R₁ is a heterocyclicgroup, R₂ is ethyl which is substituted with carboxylic acid, and X isoxygen are selected from the group consisting of:

[0445] 2-[[(2-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0446] 2-[[(3-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0447] 2-[[(4-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0448] 2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0449] 2-[[(2-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0450] 2-[[(3-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0451] 2-[[(4-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0452] 2-[[(2-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;

[0453] 2-[[(3-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid; and

[0454] 2-[[(4-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid.

[0455] Compounds of the present invention wherein R₁ is a heterocyclicgroup, R₂ is phenyl, and X is oxygen are selected from the groupconsisting of:

[0456] 2-[[(2-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0457] 2-[[(3-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0458] 2-[[(4-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0459] 2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]-2-phenylethanoicacid;

[0460] 2-[[(2-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0461] 2-[[(3-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0462] 2-[[(4-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0463] 2-[[(2-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;

[0464] 2-[[(3-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid; and

[0465] 2-[[(4-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid.

[0466] Compounds are also preferably selected from the group of formulaIII:

[0467] wherein

[0468] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; and

[0469] R₂ is Ar₁, wherein said aryl group may be optionally substitutedwith carboxylic acid.

[0470] Particular species wherein R₂ is heterocyclic may be easily madeand used by persons of ordinary skill in the art in accordance with theteachings provided herein and known in the art.

[0471] Compounds of the present invention wherein R₁ is benzyl, R₂ is aheterocyclic group, and X is oxygen are selected from the groupconsisting of:

[0472] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)ethanoic acid;

[0473] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethanoic acid;

[0474] 2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)ethanoic acid;

[0475] 2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl)ethanoicacid;

[0476] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)ethanoic acid;

[0477] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethanoic acid;

[0478] 2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)ethanoic acid;

[0479] 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)ethanoic acid;

[0480] 2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethanoic acid; and

[0481] 2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)ethanoic acid.

[0482] Preferred phosphoramidate compounds are selected from formula IV:

[0483] wherein

[0484] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; and

[0485] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid.

[0486] In a preferred embodiment, the R groups are straight branchedaliphatic or carbocyclic substituents illustrated by the compoundsselected from the group of formula IV:

[0487] wherein

[0488] R₁ is hydrogen, C₁C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, 1-naphthyl, 2-naphthyl, or phenyl; and

[0489] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl,1-naphthyl, 2-naphthyl, or phenyl, wherein said alkyl, alkenyl,cycloalkyl, cycloalkenyl, 1-naphthyl, 2-naphthyl, or phenyl group may beoptionally substituted with carboxylic acid.

[0490] Especially preferred compounds of Formula IV of the presentinvention wherein R₁ is a straight or branched aliphatic group or acarbocyclic group, R₂ is ethyl which is substituted with a carboxylicacid, and the NR₁ is amino are selected from the group consisting of:

[0491] 2-[[methylhydroxyphosphinyl]amino]pentanedioic acid;

[0492] 2-[[ethylhydroxyphosphinyl]amino]pentanedioic acid;

[0493] 2-[[propylhydroxyphosphinyl]amino]pentanedioic acid;

[0494] 2-[[butylhydroxyphosphinyl]amino]pentanedioic acid;

[0495] 2-[[cyclohexylhydroxyphosphinyl]amino]pentanedioic acid;

[0496] 2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0497] 2-[[phenylhydroxyphosphinyl]amino]pentanedioic acid;

[0498] 2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;

[0499] 2-[[phenylethylhydroxyphosphinyl]amino]pentanedioic acid;

[0500] 2-[[phenylpropylhydroxyphosphiny]amino]pentanedioic acid;

[0501] 2-[[phenylbutylhydroxyphosphinyl]amino]pentanedioic acid;

[0502] 2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0503] 2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0504] 2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0505] 2-[[(pentafluorobenzyl)hydroxyphosphinyl amino]pentanedioic acid;

[0506] 2-[[(methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0507] 2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0508] 2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino]pentanedioicacid;

[0509] 2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0510] 2-[(phosphono)amino]pentanedioic acid;

[0511] 2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino]pentanedioicacid;

[0512] 2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]amino]pentanedioicacid;

[0513] 2-[[(1-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0514] 2-[[(2-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0515] 2-[[(1-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0516] 2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0517] 2-[[(1-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

[0518] 2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

[0519] 2-[[(1-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

[0520] 2-[[(2-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

[0521] 2-[[(1-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;

[0522] 2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;and

[0523] 2-[[(phenylprop-2-enyl)hydroxyphosphinyl]amino]pentanedioic acid.

[0524] Especially preferred compounds of Formula IV of the presentinvention wherein R₁ is a straight or branched aliphatic group or acarbocyclic group, R₂ is ethyl which is substituted with a carboxylicacid, and the NR₁ is amino are selected from the group consisting of:

[0525] 2-[(benzylhydroxyphosphinyl)amino]pentanedioic acid;

[0526] 2-[(phenylhydroxyphosphinyl)amino]pentanedioic acid;

[0527] 2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino]pentanedioicacid;

[0528] 2-[(butylhydroxyphosphinyl)amino]pentanedioic acid;

[0529] 2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0530] 2-[(3-phenylpropylhydroxyphosphinyl)amino]pentanedioic acid;

[0531] 2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0532] 2-[(methylhydroxyphosphinyl)amino]pentanedioic acid;

[0533] 2-[(phenylethylhydroxyphosphinyl)amino]pentanedioic acid;

[0534] 2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0535] 2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0536] 2-[[(4-methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0537] 2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0538] 2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0539] 2-[(phosphono)amino]pentanedioic acid; and

[0540] 2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino]pentanedioicacid.

[0541] Compounds of the present invention wherein R₁ is a straight orbranched aliphatic group or a carbocyclic group, R₂ is phenyl, and X isamino are selected from the group consisting of:

[0542] 2-[[methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0543] 2-[[ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0544] 2-[[propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0545] 2-[[butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0546] 2-[[cyclohexylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0547] 2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0548] 2-[[phenylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0549] 2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0550] 2-[[phenylethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0551] 2-[[phenylpropylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0552] 2-[[phenylbutylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0553]2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0554] 2-[[(1-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0555] 2-[[(2-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0556] 2-[[(1-naphthyl)methylhydroxyphosphinyl)]amino]-2-phenylethanoicacid;

[0557] 2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0558] 2-[[(1-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0559] 2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0560] 2-[[(1-naphthyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0561] 2-[[(2-naphthyl}propylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0562] 2-[[(1-naphthyl)butylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0563] 2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]-2-phenylethanoicacid; and

[0564] 2-[[phenylprop-2-enylhydroxyphosphinyl]amino]-2-phenylethanoicacid.

[0565] Although not limited to any one particular species, a highlypreferred phosphoramidate species where R₁ is aliphatic or carbocyclic,R₂ is ethyl which is substituted with carboxylic acid, and X is amino is2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid.

[0566] Other especially preferred compounds are selected from the groupconsisting of: phosphoramidate derivatives wherein X is amino, R₁ is astraight or branched aliphatic group or a carbocyclic group, and R₂ isan C₂-C₈ alkyl or alkenyl chain which is substituted with a carboxylicacid. Exemplary species include:

[0567] 2-[(methylhydroxyphosphinyl)amino]hexanedioic acid;

[0568] 2-[(benzylhydroxyphosphinyl)amino]hexanedioic acid;

[0569] 2-[(methylhydroxyphosphinyl)amino]heptanedioic acid;

[0570] 2-[(benzylhydroxyphosphinyl)amino]heptanedioic acid;

[0571] 2-[(methylhydroxyphosphinyl)amino]octanedioic acid;

[0572] 2-[(benzylhydroxyphosphinyl)amino]octanedioic acid;

[0573] 2-[(methylhydroxyphosphinyl)amino]nonanedioic acid;

[0574] 2-[(benzylhydroxyphosphinyl)amino]nonanedioic acid;

[0575] 2-[(methylhydroxyphosphinyl)amino]decanedioic acid; and

[0576] 2-[(benzylhydroxyphosphinyl)amino]decanedioic acid.

[0577] Other especially preferred compounds are selected from the groupconsisting of:

[0578] phosphoramidate derivatives wherein X is amino, R₁ is benzyl, andR₂ is a straight or branched aliphatic group or a carbocyclic group.Exemplary species include:

[0579] 2-[[benzylhydroxyphosphinyl]amino]-2-methylethanoic acid;

[0580] 2-[[benzylhydroxyphosphinyl]amino]-2-ethylethanoic acid;

[0581] 2-[[benzylhydroxyphosphinyl]amino]-2-propylethanoic acid;

[0582] 2-[[benzylhydroxyphosphinyl]amino]-2-butylethanoic acid;

[0583] 2-[[benzylhydroxyphosphinyl]amino]-2-cyclohexylethanoic acid;

[0584] 2-[[benzylhydroxyphosphinyl]amino]-2-(cyclohexyl)methylethanoicacid;

[0585] 2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0586] 2-[[benzylhydroxyphosphinyl]amino]-2-benzylethanoic acid;

[0587] 2-[[benzylhydroxyphosphinyl]amino]-2-phenylethylethanoic acid;

[0588] 2-[[benzylhydroxyphosphinyl]amino]-2-phenylpropylethanoic acid;

[0589] 2-[[benzylhydroxyphosphinyl]amino]-2-phenylbutylethanoic acid;

[0590]2-[[benzylhydroxyphosphinyl]amino]-2-(2,3,4-trimethoxyphenyl)ethanoicacid;

[0591] 2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)ethanoic acid;

[0592] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethanoic acid;

[0593] 2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)methylethanoicacid;

[0594] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)methylethanoicacid;

[0595] 2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)ethylethanoicacid;

[0596] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethylethanoicacid;

[0597] 2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)propylethanoicacid;

[0598] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)propylethanoicacid;

[0599] 2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)butylethanoicacid;

[0600] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)butylethanoicacid; and

[0601] 2-[[benzylhydroxyphosphinyl]amino]-2-phenylprop-2-enylethanoicacid.

[0602] Especially preferred methods utilize compounds wherein R₁ is saidalkyl, alkenyl, cycloalkyl, or aryl group which is substituted with aheterocyclic group, R₂ is ethyl which is substituted with carboxylicacid, and X is amino are selected from the group consisting of:

[0603] 2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0604] 2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0605] 2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0606] 2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

[0607] 2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

[0608] 2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]pentanedioicacid;

[0609] 2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]pentanedioicacid;

[0610] 2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]pentanedioicacid;

[0611] 2-[[(2-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0612] 2-[[(3-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0613] 2-[[(4-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0614] 2-[[(3-indolyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;

[0615] 2-[[(3-indolyl)propylhydroxyphosphinyl]amino]pentanedioic acid;

[0616] 2-[[(2-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0617] 2-[[(3-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0618] 2-[[(4-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;

[0619] 2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;and

[0620] 2-[[(3-thienyl)propylhydroxyphosphinyl]amino]pentanedioic acid.

[0621] Especially preferred methods utilize compounds wherein R₁ is saidalkyl, alkenyl, cycloalkyl, or aryl group which is substituted with aheterocyclic group, R₂ is phenyl, and X is amino are selected from thegroup consisting of:

[0622] 2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0623] 2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0624] 2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0625] 2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0626] 2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0627]2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0628]2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0629]2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0630] 2-[[(2-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0631] 2-[[(3-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0632] 2-[[(4-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0633] 2-[[(3-indolyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0634] 2-[[(3-indolyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0635] 2-[[(2-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0636] 2-[[(3-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0637] 2-[[(4-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0638] 2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid; and

[0639] 2-[[(3-thienyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid.

[0640] Especially preferred methods utilize compounds wherein R₁ isbenzyl, R₂ is said alkyl, alkenyl, cycloalkyl, or aryl group which issubstituted with a heterocyclic group, and X is amino are selected fromthe group consisting of:

[0641] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)methylethanoicacid;

[0642] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)methylethanoicacid;

[0643] 2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)methylethanoicacid;

[0644] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethylethanoicacid;

[0645] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)propylethanoicacid;

[0646]2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl)methylethanoicacid;

[0647] 2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl)ethylethanoic acid;

[0648]2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl)propylethanoicacid;

[0649] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)methylethanoicacid;

[0650] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)methylethanoicacid;

[0651] 2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)methylethanoicacid;

[0652] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethylethanoicacid;

[0653] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)propylethanoicacid;

[0654] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)methylethanoicacid;

[0655] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)methylethanoicacid;

[0656] 2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)methylethanoicacid;

[0657] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethylethanoicacid; and

[0658] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)propylethanoicacid.

[0659] In another preferred embodiment, R₁ is a heterocyclic substituentillustrated by the compounds selected from the group of formula IV:

[0660] wherein

[0661] R₁ is Ar₁; and

[0662] R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid.

[0663] Especially preferred compounds wherein R₁ is a heterocyclicgroup, R₂ is ethyl which is substituted with carboxylic acid, and X isamino are selected from the group consisting of:

[0664] 2-[[(2-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0665] 2-[[(3-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0666] 2-[[(4pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0667] 2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0668] 2-[[(2-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0669] 2-[[(3-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0670] 2-[[(4-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0671] 2-[[(2-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;

[0672] 2-[[(3-thienyl)hydroxyphosphinyl]amino]pentanedioic acid; and

[0673] 2-[[(4-thienyl)hydroxyphosphinyl]amino]pentanedioic acid.

[0674] Compounds of the present invention wherein R₁ is a heterocyclicgroup, R₂ is phenyl, and X is amino are selected from the groupconsisting of:

[0675] 2-[[(2-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0676] 2-[[(3-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0677] 2-[[(4-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0678] 2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]-2-phenylethanoicacid;

[0679] 2-[[(2-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0680] 2-[[(3-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0681] 2-[[(4-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0682] 2-[[(2-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;

[0683] 2-[[(3-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;and

[0684] 2-[[(4-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid.

[0685] Compounds are also preferably selected from the group of formulaIV:

[0686] wherein

[0687] R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; and

[0688] R₂ is Ar₁, wherein said aryl group may be optionally substitutedwith carboxylic acid.

[0689] Particular species wherein R₂ is heterocyclic may be easily madeand used by persons of ordinary skill in the art in accordance with theteachings provided herein and known in the art.

[0690] Compounds of the present invention wherein R₁ is benzyl, R₂ isheterocyclic, and X is amino are selected from the group consisting of:

[0691] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)ethanoic acid;

[0692] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethanoic acid;

[0693] 2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)ethanoic acid;

[0694] 2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl)ethanoicacid;

[0695] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)ethanoic acid;

[0696] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethanoic acid;

[0697] 2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)ethanoic acid;

[0698] 2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)ethanoic acid;

[0699] 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethanoic acid;and

[0700] 2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)ethanoic acid.

Synthesis of Compounds

[0701] The compounds of the present invention can be readily prepared bystandard techniques of organic chemistry, utilizing the generalsynthetic pathways depicted below (see Schemes I-IX). Precursorcompounds may be prepared by methods known in the art, such as thosedescribed in the method of Jackson et al. (J. Med. Chem. 39(2), 619-622,Design, Synthesis, and Biological Activity of a Potent Inhibitor of theNeuropeptidase N-Acetylated a-Linked Acidic Dipeptidase) and, forexample, in Froestl et al. (J. Med. Chem., 1995, 38, 3313-3331,Phosphinic Acid Analogues of GABA).

[0702] Production of compounds containing the R group substitutions canbe easily made utilizing known methods. Further methods of synthesizingphosphinic acid esters are also described in J. Med. Chem., 1988, 31,204-212, and may be found in Scheme II, below.

[0703] Starting with the aforemnentioned phosphinic acid esters, thereare a variety of routes that can be used to prepare the compounds of thepresent invention. For example, a general route was recently describedin J. Med. Chem., 1996, 39, 619-622, and is set forth below in SchemeIII.

[0704] Another route for preparing the compounds of the presentinvention is as set forth below in scheme IV and Scheme V. Scheme IV andScheme V also show a phosphinic acid derivative as a starting materialto prepare the compounds of the present invention and the R group iscontemplated as including any reasonable chemical substitution andincludes without limitation the R groups listed in Scheme II and withinthe specification.

[0705] Another route of preparing the compounds of the present inventionallows for aromatic substitution at R1 and is set forth below in SchemeVI.

[0706] Another route of preparing the compounds of the present inventionallows for aromatic substitution at the R2 position and is set forthbelow in Scheme VII.

[0707] Preparation of the compounds of the present invention wherein Xis NR1 is set forth below in Scheme VIII.

[0708] Preparation of the compounds of the present invention wherein Xis oxygen is set forth below in Scheme IX.

Pharmaceutical Compositions of the Present Invention

[0709] The present invention also relates to a pharmaceuticalcomposition comprising:

[0710] (i) a therapeutically effective amount of a compound of formulasI, II, III or IV; and

[0711] (ii) a pharmaceutically acceptable carrier.

[0712] In another preferred embodiment, the pharmaceutical compositionfurther comprises a therapeutic agent selected from the group consistingof therapeutic hormones, chemotherapeutic agents, monoclonal antibodies,anti-angiogenesis agents, radiolabelled compounds, antineoplastic agentsand mixtures thereof. Examples of therapeutic hormones includediethylstilbestrol (DES), leuprolide, flutamide, cyproterone acetate,ketoconazole and amino glutethimide are preferred. Examples ofantineoplastic agents include 5-fluorouracil, vinblastine sulfate,estramustine phosphate, suramin and strontium-89. Examples ofchemotherapeutic agents include buserelin, chlorotranisene, chromicphosphate, cisplatin, cyclophosphamide, dexamethasone, doxorubicin,estradiol, estradiol valerate, estrogens conjugated and esterified,estrone, ethinyl estradiol, floxuridine, goserelin, hydroxyurea,melphalan, methotrexate, mitomycin and prednisone.

[0713] In a further preferred embodiment, the compound of formula I, II,III or IV is present in an amount that is effective for inhibitingNAALADase activity in an animal or treating a prostate disease in ananimal.

Process for Preparing Pharmaceutical Compositions

[0714] In yet another preferred embodiment, a process for preparing apharmaceutical composition or medicament containing a compound of thepresent invention for treating a disease is also contemplated.

Methods of Use of the Present Invention

[0715] i) Method of inhibiting NAALADase enzyme activity

[0716] The present invention further relates to a method of inhibitingNAALADase enzyme activity in an animal, comprising administering aneffective amount of a compound of formula I, II, III or IV to saidanimal.

[0717] ii) Method of treating a prostate disease

[0718] The present invention also relates to a method of treating aprostate disease in an animal, comprising administering an effectiveamount of a compound of formula I, II, III or IV to said animal.

[0719] In a preferred embodiment, said prostate disease is prostatecancer such as prostatic adenocarcinoma, benign prostatic hyperplasia,or conditions involving the prostate requiring administration of thecompounds of the present invention, such prostatic intraepithelialneoplasia (PIN).

[0720] iii) Method of treating cancer

[0721] In addition to prostate cancer, other forms of cancer that may betreated with the compounds of the present invention include withoutlimitation: ACTH-producing tumors, acute lymphocytic leukemia, acutenonlymphocytic leukemia, cancer of the adrenal cortex, bladder cancer,brain cancer, breast cancer, cervix cancer, chronic lymphocyticleukemia, chronic myelocytic leukemia, colorectal cancer, cutaneousT-cell lymphoma, endometrial cancer, esophageal cancer, Ewing's sarcoma,gallbladder cancer, hairy cell leukemia, head & neck cancer, Hodgkin'slymphoma, Kaposi's sarcoma, kidney cancer, liver cancer, lungcancer(small and/or non-small cell), malignant peritoneal effusion,malignant pleural effusion, melanoma, mesothelioma, multiple myeloma,neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovary(germ cell) cancer, pancreatic cancer, penis cancer, retinoblastoma,skin cancer, soft-tissue sarcoma, squamous cell carcinomas, stomachcancer, testicular cancer, thyroid cancer, trophoblastic neoplasms,cancer of the uterus, vaginal cancer, cancer of the vulva and Wilm'stumor.

[0722] The compounds of the present invention are particularly useful intreating cancer of tissues where NAALADase enzymes reside. Such tissuesinclude the prostate as well as the brain, kidney and testis.

[0723] For patients who initially present without advanced or metastaticcancer, NAALADase inhibitor based drugs are used as an immediate initialtherapy prior to surgery and radiation therapy, and as a continuouspost-treatment therapy in patients at risk for recurrence or metastasis(based upon high PSA, high Gleason's score, locally extensive disease,and/or pathological evidence of tumor invasion in the surgicalspecimen). The goal in these patients is to inhibit the growth ofpotentially metastatic cells from the primary tumor during surgery orradiotherapy and inhibit the growth of tumor cells from undetectableresidual primary tumor.

[0724] For patients who initially present with advanced or metastaticcancer, NAALADase inhibitor based drugs are used as a continuoussupplement to, or possible as a replacement for hormonal ablation. Thegoal in these patients is to slow tumor cell growth from both theuntreated primary tumor and from the existing metastatic lesions.

[0725] In addition, the invention may be particularly efficacious duringpost-surgical recovery, where the present compositions and methods maybe particularly effective in lessening the chances of recurrence of atumor engendered by shed cells that cannot be removed by surgicalintervention.

[0726] iv) Diagnostic kits

[0727] The present invention also includes a diagnostic kit forperforming the methods of the present invention and may containcompounds and/or compositions containing the compounds of the presentinvention. Radiolabelled compounds and monoclonal antibodies may be usedin a manner so as to provide diagnostic information. Examples ofdiagnostic information and uses include determining the type of disease,the progress of the particular disease, the location of cells targetedby a NAALADase inhibitor, radiolabelled compound or monoclonal antibody,and similar diagnostic uses known to persons skilled in the art.

Route of Administration

[0728] In the methods of the present invention, the compounds may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir indosage formulations containing conventional non-toxicpharmaceutically-acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous, intravenous,intramuscular, intraperitoneal, intrathecal, intraventricular,intrasternal or intracranial injection and infusion techniques. Invasivetechniques are preferred, particularly direct administration to damagedneuronal tissue.

[0729] To be effective therapeutically as central nervous systemtargets, the compounds of the present invention should readily penetratethe blood-brain barrier when peripherally administered. Compounds whichcannot penetrate the blood-brain barrier can be effectively administeredby an intraventricular route.

[0730] The compounds may also be administered in the form of sterileinjectable preparations, for example, as sterile injectable aqueous oroleaginous suspensions. These suspensions can be formulated according totechniques known in the art using suitable dispersing or wetting agentsand suspending agents. The sterile injectable preparations may also besterile injectable solutions or suspensions in non-toxicparenterally-acceptable diluents or solvents, for example, as solutionsin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile fixed oils are conventionally employed assolvents or suspending mediums. For this purpose, any bland fixed oilsuch as a synthetic mono- or di-glyceride may be employed. Fatty acidssuch as oleic acid and its glyceride derivatives, including olive oiland castor oil, especially in their polyoxyethylated forms, are usefulin the preparation of injectables. These oil solutions or suspensionsmay also contain long-chain alcohol diluents or dispersants.

[0731] Additionally, the compounds may be administered orally in theform of capsules, tablets, aqueous suspensions or solutions. Tablets maycontain carriers such as lactose and corn starch, and/or lubricatingagents such as magnesium stearate. Capsules may contain diluentsincluding lactose and dried corn starch. Aqueous suspensions may containemulsifying and suspending agents combined with the active ingredient.The oral dosage forms may further contain sweetening and/or flavoringand/or coloring agents.

[0732] The compounds may further be administered rectally in the form ofsuppositories. These compositions can be prepared by mixing the drugwith suitable non-irritating excipients which are solid at roomtemperature, but liquid at rectal temperature such that they will meltin the rectum to release the drug. Such excipients include cocoa butter,beeswax and polyethylene glycols.

[0733] Moreover, the compounds may be administered topically, especiallywhen the conditions addressed for treatment involve areas or organsreadily accessible by topical application, including neurologicaldisorders of the eye, the skin or the lower intestinal tract.

[0734] For topical application to the eye, or ophthalmic use, thecompounds can be formulated as micronized suspensions in isotonic, pHadjusted sterile saline or, preferably, as a solution in isotonic, pHadjusted sterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, the compounds may be formulatedinto ointments, such as petrolatum.

[0735] For topical application to the skin, the compounds can beformulated into suitable ointments containing the compounds suspended ordissolved in, for example, mixtures with one or more of the following:mineral oil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the compounds can be formulated into suitable lotions orcreams containing the active compound suspended or dissolved in, forexample, a mixture of one or more of the following: mineral oil,sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

[0736] Topical application to the lower intestinal tract can be effectedin rectal suppository formulations (see above) or in suitable enemaformulations.

[0737] The compounds of the present invention may be administered by asingle dose, multiple discrete doses or continuous infusion. Since thecompounds are small, easily diffusible and relatively stable, they arewell suited to continuous infusion. Pump means, particularlysubcutaneous pump means, are preferred for continuous infusion.

[0738] Compositions and methods of the invention also may utilizecontrolled release technology. Thus, for example, NAALADase inhibitorsmay be incorporated into a polymer matrix for controlled release over aperiod of days. Such controlled release films are well known to the art.Examples of polymers commonly employed for this purpose that may be usedin the present invention include nondegradable ethylene-vinyl acetatecopolymer and degradable lactic acid-glycolic acid copolymers. Certainhydrogels such as poly(hydroxyethylmethacrylate) or poly(vinylalcohol)also may be useful.

Dosage

[0739] Dose levels on the order of about 0.1 mg to about 10,000 mg ofthe active ingredient compound are useful in the treatment of the aboveconditions, with preferred levels being about 0.1 mg to about 1,000 mg.The specific dose level for any particular patient will vary dependingupon a variety of factors, including the activity of the specificcompound employed; the age, body weight, general health, sex and diet ofthe patient; the time of administration; the rate of excretion; drugcombination; the severity of the particular disease being treated; andthe form of administration. Typically, in vitro dosage-effect resultsprovide useful guidance on the proper doses for patient administration.Studies in animal models are also helpful, particularly in determiningeffective doses for treating cancer. The considerations for determiningthe proper dose levels are well known in the art.

[0740] In a preferred embodiment, the compounds of the present inventionare administered in lyophilized form. In this case, 1 to 100 mg of acompound of the present invention may be lyophilized in individualvials, together with a carrier and a buffer, such as mannitol and sodiumphosphate. The compound may be reconstituted in the vials withbacteriostatic water before administration.

[0741] As previously mentioned, the compounds of the present inventionmay be administered in combination with one or more therapeutic agents,including chemotherapeutic agents. TABLE I provides known median dosagesfor selected chemotherapeutic agents. Specific dose levels for theseagents will depend upon considerations such as those identified abovefor the compounds of the present invention. TABLE I CHEMOTHERAPEUTICAGENT MEDIAN DOSAGE Asparaginase 10,000 units Bleomycin Sulfate 15 unitsCarboplatin 50-450 mg Carmustine 100 mg Cisplatin 10-50 mg Cladribine 10mg Cyclophosphamide 100 mg-2 gm (lyophilized) Cyclophosphamide (non- 100mg-2 gm lyophilized) Cytarabine (lyophilized 100 mg-2 gm powder)Dacarbazine 100 mg-200 mg Dactinomycin 0.5 mg Daunorubicin 20 mgDiethylstilbestrol 250 mg Doxorubicin 10-150 mg Etidronate 300 mgEtoposide 100 mg Floxuridine 500 mg Fludarabine Phosphate 50 mgFluorouracil 500 mg-5 gm Goserelin 3.6 mg Granisetron Hydrochloride 1 mgIdarubicin 5-10 mg Ifosfamide 1-3 gm Leucovorin Calcium 50-350 mgLeuprolide 3.75-7.5 mg Mechlorethamine 10 mg Medroxyprogesterone 1 gmMelphalan 50 gm Methotrexate 20 mg-1 gm Mitomycin 5-40 mg Mitoxantrone20-30 mg Ondansetron Hydrochloride 40 mg Paclitaxel 30 mg PamidronateDisodium 30-*90 mg Pegaspargase 750 units Plicamycin 2,500 mcgmStreptozocin 1 gm Thiotepa 15 mg Teniposide 50 mg Vinblastine 10 mgVincristine 1-5 mg Aldesleukin 22 million units Epoetin Alpha2,000-10,000 units Filgrastim 300-480 mcgm Immune Globulin 500 mg-10 gmInterferon Alpha-2a 3-36 million units Interferon Alpha-2b 3-50 millionunits Levamisole 50 mg Octreotide 1,000-5,000 mcgm Sargramostim 250-500mcgm

Administration Regimen

[0742] For the methods of the present invention, any administrationregimen regulating the timing and sequence of drug delivery can be usedand repeated as necessary to effect treatment. Such regimen may includepretreatment and/or co-administration with additional therapeuticagents.

[0743] For patients with prostate cancer that is neither advanced normetastatic, the compounds of the present invention may be administered(i) prior to surgery or radiation treatment to reduce the risk ofmetastasis; (ii) during surgery or in conjunction with radiationtreatment; and/or (iii) after surgery or radiation therapy to reduce therisk of recurrence and to inhibit the growth of any residual tumorouscells.

[0744] For patients with advanced or metastatic prostate cancer, thecompounds of the present invention may be administered as a continuoussupplement to, or as a replacement for, hormonal ablation in order toslow tumor cell growth in both the untreated primary tumor and theexisting metastatic lesions.

[0745] The methods of the present invention are particularly usefulwhere shed cells could not be removed by surgical intervention. Afterpost-surgical recovery, the methods of the present invention would beeffective in reducing the chances of recurrence of a tumor engendered bysuch shed cells.

Combination with Other Treatments

[0746] (i) Surgery and Radiation Treatment

[0747] In general, surgery and radiation treatment are employed aspotentially curative therapies for patients with localized prostatecancer who are under 70 years of age and are expected to live at least10 more years.

[0748] Approximately 70% of newly diagnosed prostate cancer patientsfall into this category. Approximately 90% of these patients (65% oftotal patients) undergo surgery, while approximately 10% of thesepatients (7% of total patients) undergo radiation treatment.

[0749] Histopathological examination of surgical specimens reveals thatapproximately 63% of patients undergoing surgery (40% of total patients)have locally extensive tumors or regional (lymph node) metastasis thatwas undetected at initial diagnosis. These patients are at asignificantly greater risk of recurrence. Approximately 40% of thesepatients will actually develop recurrence within five years aftersurgery. Results after radiation treatment are even less encouraging.Approximately 80% of patients who have undergone radiation treatment astheir primary therapy have disease persistence or develop recurrence ormetastasis within five years after treatment.

[0750] Currently, most prostate cancer patients undergoing surgery andradiation treatment do not receive any immediate follow-up therapy.Rather, they are monitored frequently for elevated Prostate SpecificAntigen (“PSA”), which is the primary indicator of recurrence ormetastasis.

[0751] Based on the above statistics, there is considerable opportunityto use the present invention in conjunction with surgery and/orradiation treatment.

[0752] (ii) Hormonal Therapy

[0753] Hormonal ablation is the most effective palliative treatment forthe 10% of patients with metastatic prostate cancer. Hormonal ablationby medication and/or orchiectomy is used to block hormones that promotefurther growth and metastasis of prostate cancer. With time, both theprimary and metastatic tumors of virtually all of these patients becomehormone-independent and resistant to therapy. Approximately 50% ofpatients with metastatic cancer die within three years after initialdiagnosis, and 75% of such patients die within five years afterdiagnosis. Continuous supplementation with the compounds of the presentinvention may be used to prevent or reverse this potentiallymetastasis-permissive state.

[0754] (iii) Chemotherapy

[0755] While chemotherapy has been successful in treating some forms ofcancer, it has shown slight therapeutic value in treating prostatecancer where it is generally reserved as a last resort. Accordingly, theopportunity to treat prostate cancer by combining chemotherapy with themethods of the present invention will be rare. When combined, however,such treatments should be more effective than chemotherapy alone incontrolling prostate cancer.

[0756] (iv) Immunotherapy

[0757] The compounds of the present invention may also be used incombination with monoclonal antibodies to treat prostate cancer. Suchcombined treatment is particularly effective for patients with pelviclymph node involvement, of which only 34% survive after 5 years. Anexample of such monoclonal antibodies is cell membrane-specificanti-prostate antibody.

[0758] The present invention may also be used with immunotherapies basedon polyclonal or monoclonal antibody-derived reagents. Monoclonalantibody-derived reagents are preferred. These reagents are well knownin the art, and include radiolabelled monoclonal antibodies such asmonoclonal antibodies conjugated with strontium-89.

[0759] (v) Cryotherapy

[0760] The methods of the present invention may also be used inconjunction with cryotherapy for treatment of prostate cancer.

Experimental Studies

[0761] The following experimental studies of compounds of the presentinvention and of structurally related compounds provide strong evidencethat the compounds of the present invention are non-toxic and areeffective in inhibiting NAALADase activity, treating glutamateabnormalities and treating prostate diseases.

In Vivo Toxicity of NAALADase Inhibitors

[0762] To examine the toxicological effect of NAALADase inhibition invivo, a group of mice were injected with 2-(phosphonomethyl)pentanedioicacid, a NAALADase inhibitor of high activity, in doses of 1, 5, 10, 30,100, 300 and 500 mg/kg body weight. The mice were subsequently observedtwo times per day for 5 consecutive days. The survival rate at each doselevel is provided in TABLE II below. The results show that the NAALADaseinhibitor is non-toxic to mice, suggesting that the compounds of thepresent invention would be similarly non-toxic to humans whenadministered at therapeutically effective amounts. TABLE IITOXICOLOGICAL EFFECTS OF NAALADASE INHIBITORS Dose 1 5 10 30 100 300 500(mg/kg) Survival 100 100 100 100 100 100 66.7 Rate After 5 days (%)

In Vitro Assay of NAALADase Activity

[0763] The following compounds were tested for in vitro inhibition ofNAALADase activity. The results are provided in Tables III(a), III(b),and III(c) below. TABLE III (a) IN VITRO ACTIVITY OF NAALADASEINHIBITORS Compound K_(i) (nM) 2- (phosphonomethyl)pentanedioic acid 0.275 ± 0.08 2-(phosphonomethyl)succinic acid 700.00 ± 67.3 2-[[2-carboxyethyl)hydroxyphosphinyl]  1.89 ± 0.19 methyl]pentanedioicacid)

[0764] 2-(phosphonomethyl)pentanedioic acid showed a high level ofNAALADase inhibiting activity, with a K_(i) of 0.27 nM (Table III(a)).The activity of this compound is >1000 times more potent than that ofpreviously described inhibitors. Since 2-(phosphonomethyl)pentanedioicacid is similar in structure to the compounds of the present invention,the results suggest that the compounds of the present invention wouldalso be potent NAALADase inhibitors. By comparison,2-(phosphonomethyl)succinic acid exhibits much lower NAALADaseinhibiting activity, suggesting that a glutamate analog attached to thephosphonic acid contributes to its NAALADase inhibiting activity. Theresults also show that2-[[2-carboxyethyl)-hydroxyphosphinyl]methyl]pentanedioic acid, whichhas an additional carboxylic acid side chain similar to the aspartateresidue found in NAAG, exhibits a lower NAALADase inhibiting activitythan 2-(phosphonomethyl)-pentanedioic acid.

Table III(b)

[0765] Other compounds demonstrating inhibition of NAALADase activityare set forth below in Table III(b). Results of the nine compounds inTable III(b) shows the remarkable Ki activity of a variety of compoundsof the present invention. These compounds show NAALADase inhibitoryability wherein R1 comprises an aliphatic group, a aliphatic which issubstituted, an aromatic group, and aromatic which is substituted. TABLEIII (b) In vitro Activity of NAALADase Inhibitors COMPOUND Ki(nM)COMPOUND Ki(nM)

34

231

36

532

54

1100 

148 

148

190 

[0766] Further results, provided in Table III(c), show the remarkable Kiactivity of the compounds of the present invention. These compounds showNAALADase inhibition wherein R1 comprises a substituted aliphatic(benzyl) which is further substituted. TABLE III (c) in vitro Activityof NAALADase Inhibitors Compound Ki Value (nM)

Ki = 68 nM

Ki = 70 nM

Ki = 90 nM

Ki = 175 nM

Ki = 38 nM

Protocol for In Vitro Assay of NAALADase Activity

[0767] The amount of [³H]Glu liberated from [³H]NAAG in 50 mM Tris-Clbuffer was measured for 15 minutes at 37° C. using 30-50 μg ofsynaptosomal protein. Substrate and product were resolved byanion-exchange liquid chromatography. Duplicate assays were performed sothat no more than 20% of the NAAG was digested, representing the linearrange of peptidase activity. Quisqualate (100 μM) was included inparallel assay tubes to confirm the specificity of the measurements.

In Vitro Assay of NAALADase Inhibitors on Cancer

[0768] Referring now to FIGS. 1 and 2, the effect of NAALADaseinhibitors on cancer cell line were examined. LNCAP cells (a prostatecancer cell line) were treated with quisqualate acid (in concentrationsranging from 10 nM to 1 μM) and 2-(phosphonomethyl)pentanedioic acid (inconcentrations ranging from 100 pM to 10 nM). The 3H-thymidinemeasurement for each concentration of quisqualate acid and2-(phosphonomethyl)pentanedioic acid is also provided in TABLE IV below.FIGS. 1 and 2 present this data graphically and particularly illustratethe decrease in proliferation and thymidine uptake of cells treated withNAALADase inhibitors. TABLE IV 3H-Thymidine Incorooration (dpm/well)2-(phosphonomethyl)- Dose Quisqualic Acid pentanedioic acid Control 4813± 572 4299 ± 837   10 pM — 3078 ± 1006 100 pM — 2062 ± 595   1 nM 3668 ±866 1001 ± 52   10 nM 2137 ± 764 664 ± 366 100 nM 1543 ± 312 —  1 μM1295 ± 181 —

[0769] The results show that LNCAP cell proliferation (as measured bythe incorporation of 3H-thymidine) decreased significantly as theconcentration of the NAALADase inhibitors increased, suggesting that thecompounds of the present invention would be effective in treatingcancer, particularly prostate cancer.

Protocol for In Vitro Cancer Assay

[0770] Cells in RPMI 1640 medium containing 10% Fetal Calf Serum (FCS)are plated in 24 well plates and allowed to adhere for 24 hours beforeaddition of quisqualic acid (10⁻⁹ M to 10⁻⁶ M) or2-(phosphonomethyl)pentanedioic acid (10⁻¹¹ M to 10⁻⁸ M) for 7 days. Onthe 7th day, the cells are pulsed with 3H-thymidine for 4 hours,harvested and measured for radioactivity. Values represent means +/− SEMof 6 separate cell wells for each treatment. All experiments areperformed at least twice.

[0771] To control for non-specific cytostatic effects of quisqualateacid and 2-(phosphonomethyl)pentanedioic acid, the agents aresimultaneously evaluated on a non-NAALADase containing prostate cellline, DU145 (Carter et al., Proc. Natl. Acad. Sci. USA, (93) 749-753,1996). If the treatments with quisqualate acid and2-(phosphonomethyl)pentanedioic have no significant effect on cellgrowth, the NAALADase inhibiting activity of the agents are uniquelyresponsible for their cytostatic effects on NAALADase containingprostate carcinoma cell lines.

Cell Lines and Tissue Culture

[0772] LNCAP cells are obtained from Dr. William Nelson at the JohnsHopkins School of Medicine in Baltimore, Md. DU145 cells are obtainedfrom American Type Culture Collection (Rockville, Md.). Cells are grownin RPMI-1640 media supplemented with 10% heat-inactivated fetal calfserum, 2 mM-glutamine, 100 units/ml penicillin, and 100 pg/mlstreptomycin (Paragon) in a humidified incubator at 37° C. In a 5%CO₂/95% O₂ atmosphere.

[3H] Thymidine Incorporation Assays

[0773] The cells are suspended at 1×10³ cells/ml in RPMI-1640 media andseeded into 24-well plates at 500 μl per well. After 24 hours, variousconcentrations of quisqualic acid (Sigma) or the potent NAALADaseinhibitor 2-(phosphonomethyl)pentanedioic acid (synthesized according tothe methods of Jackson et al., J Med Chem 39(2) 619-622) is added to thewells and the plates are returned to the incubator. On days 3, 5 and 7,media and drug are refreshed. On the 8th day following seeding, eachwell is pulsed with 1 μCi ³H-thymidine (New England Nuclear) for 4hours. Media is then removed and the wells washed 2 times with phosphatebuffered saline (pH=7.4). The contents of each well is subsequentlysolubilized with 250 μl of 0.2 N NaOH and transferred to scintillationvials. 5 ml UltimaGold (Packard) scintillation cocktail is added andradioactivity is quantitated using a Beckman LS6001 scintillationcounter.

[0774] The purity and/or identity of all synthetic compounds isascertained by thin layer chromatography, High Pressure LiquidChromatography (HPLC), mass spectrometry, and elemental analysis. ProtonNuclear Magnetic Resonance (NMR) spectra are obtained using a Brukerspectrometer. Chemical shifts are reported in parts per million relativeto tetramethylsilane as internal standard. Analytical thin-layerchromatography (TLC) is conducted on prelayered silica gel GHLF plates(Analtech, Newark, Del.). Visualization of the plates is accomplished byusing UV light, phosphomolybdic acid-ethanol, and/or iodoplatinatecharring. Flash chromatography is conducted on Kieselqel 60, 230-400mesh (E. Merck, Darmstadt, West Germany). Solvents are either reagent orHPLC grade. Reactions are run at ambient temperature and under anitrogen atmosphere unless otherwise noted. Solutions are evaporatedunder reduced pressure on a Buchi rotary evaporator.

In vivo LNCaP Tumor Xenograft Assay and Results

[0775] Referring now to FIGS. 3 and 4, LNCaP human prostate cancer cellswere injected subcutaneously into the right flank of male nude mice.2-(phosphonomethyl)pentanedioic acid, a NAALADase inhibitor, wasadministered by daily intratumoral injection (0.25 μg/day) beginningwhen the tumors reached a volume of approximately 50-70 mm³. Anadditional group was included using a silicon polymer containing2-(phosphonomethyl)pentanedioic acid which released approximately 0.25μg/day of drug locally into the tumor. The2-(phosphoriomethyl)pentanedioic acid polymer was changed two times perweek. Tumor volumes were monitored for 42 days after the beginning oftreatment.

[0776] Experimental Procedures

[0777] Cell Lines

[0778] LNCaP is a human, prostate cancer cell line that was establishedin 1973 from a pleural effusion of a patient who had been treated with5-FU, doxorubicin, methotrexate, and CTX in the 3 months before the cellline was initiated. This line is androgen receptor positive and has beenused in screening anticancer drugs that are targeted as hormoneantagonists. LNCaP was grown in RPMI with 1.5 g NaHCO3/L, 10% fetalbovine serum (FES), and 2 mM L-glutamine and was kept at 37° C. In ahumidified 5% CO₂/O₂ incubator. Antibiotics were not added to themedium.

[0779] Animal Tumor Model

[0780] NCr nude (nu/nu) male mice, age 4-5 weeks, were purchased fromTaconic (Germantown, N.Y.). The animals were housed four per cage insterile filter-topped cages in a ventilated cage rack. Upon arrival,they were quarantined for four working days before use. Temperature wasmaintained at 72±5° F. and relative humidity at 35-70%, and a 12-hrlight/dark cycle is used. The mice were fed sterile, autoclavable,certified Purina rodent chow ad libitum. Drinking water was acidifiedand autoclaved, and the source water was recirculated, deionized,UV-treated, and 5-μm filtered.

[0781] After the animals were released from quarantine, the mice wereinjected subcutaneously in the right flank with 1×10⁷ LNCaP cells inMatrigel™ (0.1-ml injection volume). Tumor dimensions and body weightwere measured twice weekly. Vernier calipers were used to measure tumorsin three planes, and tumor volume (V) was calculated as follows:V=π(x×y×z)/6, where x, y, and z were the tumor measurements minus skinthickness. At the end of the experiment, the mice were sacrificed by CO₂inhalation followed by cervical dislocation.

[0782] Pharmaceuticals

[0783] 2-(phosphonomethyl)pentanedioic acid was made up in water at aconcentration of 2.5 mg/ml. Polymer containing2-(phosphonomethyl)pentanedioic acid was made up by grinding 140 mg NaClto a fine powder then mixing with 5 mg 2-(phosphonomethyl)pentanedioicacid and 350 mg silicone gel. The mixture was spread to a thin film andallowed to dry for 24 hours. The material was cut into 1-1.5 mg piecesfor subcutaneous implantation.

[0784] Treatment Protocol

[0785] When the tumor volumes reached a predetermined size (mean tumorvolume 50-70 mm³), mice were added randomly into treatment groups of sixto eight mice each. All treatments were administered daily for at least4 weeks. 2-(phosphonomethyl)pentanedioic acid was administeredintratumorally daily in a volume of 0.05 ml containing 0.025 μg2-(phosphonomethyl)pentanedioic acid per injection.

[0786] Polymer containing 2-(phosphonomethyl)pentanedioic acid (10 μgdrug/mg polymer) was implanted subcutaneously. Mice were anaesthetizedwith metafane, and a small (<2 mm) incision was made near the tumorsite. Following implantation, the incision was closed with a wound clip.Polymer was replaced twice weekly.

[0787] The tumor were measured twice weekly for at least 8 weeks afterthe first treatment. The mean tumor volume for each group was calculatedfor each time point. Comparisons between groups at specific times weremade using an unpaired, two-tailed t-test, and the results were analyzedusing analysis of variance (ANOVA)

[0788] Systemic toxicity was assessed from reductions in body weightafter treatment. The mice were sacrificed at the end of the follow-upperiod, or earlier if their tumor volumes reached 1600 mm³ or the tumorsulcerated.

[0789] Statistical Analysis

[0790] Statistical analysis as described above was performed using JMP(SAS Institute Inc., Cary, N.C.)

In vivo Rat Dunning R3327 Model

[0791] Referring now to FIGS. 5 and 6, Dunning R3327-G prostate cancercells were injected subcutaneously into both flanks of syngeneic malerats. In the first study, the anti-tumor growth activity of2-(phosphonomethyl)pentanedioic acid was tested following dailysubcutaneous injections of the drug (1, 3 10 and 30 mg/kg).2-(phosphonomethyl)pentanedioic acid injections and tumor measurementswere continued for 12 weeks. In the second study, the anti-tumor growthactivity of 2-[[phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acidwas tested following daily intra-tumoral injections of the drug (0.1, 1,10, 100 μg) after the tumor reached an initial volume of 80-290 mm³.Tumor volumes were subsequently monitored for 42 days after thebeginning of drug treatment.

[0792] Experimental Procedures

[0793] Cell Lines

[0794] R3327-G is a cell line derived from an androgen-sensitivepapillary adenocarcinoma derived from a spontaneously forming tumor inthe rat prostate. R3327-G cells were grown in RPMI, 10% fetal bovineserum (FBS), 2 mM L-glutamine, and 10-8 M dexamethasone. Cultures werekept at 37° C. In a humidified 5% CO₂/O₂ incubator. Antibiotics were notadded to the medium.

[0795] Animal Tumor Model

[0796] Copenhagen male rats, age 8-10 weeks, were purchased from HarlanSprague Dawley (Indianapolis, Ind.). The animals were housed two percage. Upon arrival, they were quarantined for four working days beforeuse. Temperature was maintained at 72±5° F. and relative humidity at35-70%, and a 12-hr light/dark cycle was used. The rats were fedcertified Purina rodent chow and water ad libitum.

[0797] After the animals were released from quarantine, the rats wereinjected subcutaneously in both flanks with 1×10⁷ R3327-G cells (0.1-mlinjection volume). Tumor dimensions and body weight were measured twiceweekly. Vernier calipers were used to measure tumors in three planes,and tumor volume (V) was calculated as follows: V=π(x×y×z)/6, where x,y, and z were the tumor measurements minus skin thickness. Tumors beganto appear 4-5 weeks after tumor cell injection. At the end of theexperiment, the rats were sacrificed by CO₂ inhalation.

[0798] Pharmaceuticals

[0799] 2-(phosphonomethyl)pentanedioic acid was made up in physiologicalsaline fresh each day prior to injection. A stock solution of2-[phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid was made upin water at a concentration 2.5 mg/ml; ten-fold serial dilutions weremade fresh weekly for injections.

[0800] Treatment Protocol

[0801] In the 2-(phosphonomethyl)pentanedioic acid study, the rats weregiven daily subcutaneous injections of drug beginning the 14 daysfollowing tumor cell implantation and continued for 12 weeks. In the2-[[phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid study, thedrug was not administered until the tumor volumes reached apredetermined size (mean tumor volume 90-290 mm³). At this time, therats were divided into treatment groups of five rats each. Alltreatments of 2-[[phenylmethyl)hydroxyphosphinyl]methyl]pentanedioicacid were subsequently administered intra-tumorally daily for 6 weeks.

[0802] The tumors were measured twice weekly. The mean tumor volume foreach group was calculated for each time point. Comparisons betweengroups at specific times were made using an unpaired, two-tailed t-test,and the results were analyzed using analyzed of variance (ANOVA). Forthe 2-[[phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid study,individual tumor volumes (V) were expressed as a fraction of the tumorvolume on Day 0, the first day of treatment (V0). For each group, themean of the ratio V/V0 was plotted as a function of time aftertreatment.

[0803] Statistical Analysis

[0804] Statistical analysis as described above was performed using JMP(SAS Institute, Inc. Cary, N.C.).

EXAMPLES

[0805] The following examples are illustrative of preferred embodimentsof methods of use and preparation of compounds of the invention and arenot to be construed as limiting the invention thereto. Unless otherwiseindicated, all percentages are based upon 100% of the finalformulations.

Example 1 Preparation of 2-[(methylhydroxyphosphinyl)methyl]pentanedioicacid

[0806] Scheme IV R=CH3, R1=CH2Ph

[0807] Methyl-O-benzylphosphinic Acid

[0808] Dichloromethylphosphite (10.0 g, 77 mmol) in 80 mL of dry diethylether was cooled to −20° C. under an atmosphere of nitrogen. A solutionof benzyl alcohol (23 g, 213 mmol) and triethylamine (10.2 g, 100 mmol)in 40 mL of diethyl ether was added dropwise over 1 hour whilemaintaining an internal temperature range of 0° C. to 10° C. Onceaddition was complete the mixture was warmed to room temperature andstirred overnight. The mixture was filtered and the solid cake washedwith 200 mL of diethyl ether. The organics were combined and evaporatedunder reduced pressure to give 25 g of a clear and colorless liquid. Theliquid was purified by flash chromatography and eluted with a 1:1hexane/ethyl acetate to ethyl acetate gradient. The desired fractionswere collected and evaporated to give methyl O-benzylphosphinic acid (1,R=CH3, R1=CH2Ph, 6.5 g, 50%) as a clear and colorless oil. Rf 0.1 (1:1,Hexane/EtOAc).

[0809]¹H NMR(d6-DMSO): 7.4 ppm (m,5H), 7.1 ppm (d,1H), 5.0 ppm (dd,2H),1.5 ppm (d,3H)

2,4-Di(benzyloxycarbonyl)butyl(methyl)-O-benzylphosphinic acid

[0810] Methyl-O-benzylphosphinic acid (3.53 g, 20.7 mmol) in 200 mL ofdichloromethane was cooled to −5° C. under an atmosphere of nitrogen.Triethylamine (3.2 g, 32 mmol) was added via syringe followed bytrimethylsilyl chloride (2.9 g, 27 mmol). The reaction mixture wasstirred and warmed to room temperature over 1 hour. Dibenzyl2-methylenepentanedioate (2, 6.0 g, 18.5 mmol) in 10 mL ofdichloromethane was added. The mixture was then stirred at roomtemperature overnight. The reaction mixture was cooled to 0° C. andtrimethylaluminum (9 mL, 18 mmol, 2.0 M in dichloromethane) was added.The flask was warmed and stirred for 72 hours. The clear light yellowsolution was cooled to 5° C. and quenched by the slow addition of 5%hydrochloric acid. The quenched reaction mixture was warmed to roomtemperature and the organic layer removed. The organic layer was washedwith 5% hydrochloric acid and with water. The organics were dried(MgSO₄) and evaporated under reduced pressure to give 8 g of a clearlight yellow oil. The oil was purified on silica gel and eluted with agradient of 1:1 hexanes/ethyl acetate to 100% ethyl acetate. The desiredfractions were collected and evaporated to give2,4-di(benzyloxycarbonyl)buty(methyl)-O-benzylphosphinic acid (3, R=CH3,R1=CH2Ph 0.8 g, 8%) as a clear and colorless oil. Rf 0.5 (ethylacetate).

[0811]¹H NMR(CDCl₃):7.4 ppm (m,15H), 5.1 ppm (m,6H), 3.0 ppm (m, 1H),2.4 ppm (m,3H),2.1 ppm (m,3H), 1.5 ppm (dd,3H)

[0812] Elemental Analysis Calculated C₂₈H₃₁O₆P.0.5H₂O:C 68.01,H 6.32Found: C 66.85,H 6.35

2-(Methylhydroxyphosphinyl)methyl]pentanedioic acid

[0813] 2,4-di(benzyloxycarbonyl)buty(methyl)-O-benzylphosphinic acid(0.8 g, 1.6 mmol) in 20 mL of water containing 100 mg of 10% Pd/C washydrogenated at 40 psi for 4 hours. The mixture was filtered over a padof Celite and evaporated at high vacuum to give2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=CH3, 0.28 g,78% as a clear and colorless viscous oil.

[0814]¹H NMR (D₂O): 2.5 ppm (m,1H), 2.2 ppm(t,2H), 2.0 ppm (m,1H), 1.7ppm(m,3H), 1.3 ppm (d, 3H)

[0815] Elemental Analysis Calculated C₇H₁₃O₆P.0.2 H₂O: C36.92 H 5.93Found: C37.06 H 6.31

Example 2 Preparation of 2-[(butylhydroxyphosphinyl)methyl]pentanedioicacid

[0816] Scheme IV R=n-butyl, R1=H

[0817] Butylphosphinic Acid

[0818] Diethyl chlorophosphite (25 g, 0.16 mol) in 60 mL of dry etherwas cooled to 0° C. under an atmosphere of nitrogen. Butylmagnesiumchloride (80 mL, 0.16 mol, 2.0 M solution in ether) was added dropwiseover a period of 2 hours while maintaining the internal temperature at0° C. Once addition was complete the thick white slurry was heated to30° C. for 1 hour. The suspension was filtered under a nitrogenatmosphere and the filtrate evaporated under reduced pressure. The clearlight yellow liquid was then brought up in 15 mL of water and stirred atroom temperature. Concentrated hydrochloric acid (0.5 mL) was then addedand an exothermic reaction was observed. The mixture was stirred anadditional 15 minutes and extracted with two 75 mL portions of ethylacetate. The organics were combined, dried (MgSO₄) and evaporated togive a clear and colorless liquid. The liquid was treated with NaOH (40mL, 20 M) and stirred for 1 hour. The mixture was then washed withdiethyl ether and acidified to pH 1.0. The desired material wasextracted from the acidified extract with two 100 mL portions of ethylacetate. The organics were combined, dried (MgSO₄) and evaporated underreduced pressure to give butylphosphinic acid (1, R=n-butyl, R1=H, 10 g,51%) as a clear and colorless liquid.

[0819] 1H NMR (d6-DMSO): 6.9 ppm(d, 1H), 1.6 ppm(m,2H), 1.4 ppm(m,4H),0.9 ppm(t,3H)

Butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid

[0820] Butylphosphinic acid (2.0 g, 16 mmol) in 80 mL of drydichloromethane was cooled to 0° C. under an atmosphere of nitrogen.Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilylchloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture wasstirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate(2) (6.4 g, 20 mmol) in 20 mL of dichloromethane was added. The coldbath was removed and the reaction warmed to room temperature and stirredovernight. The mixture was then cooled to 0° C. and quenched by the slowaddition of 5% hydrochloric acid. The dichloromethane layer was thenremoved and washed with 5% hydrochloric acid and with brine. The organiclayer was dried (MgSO₄) and evaporated to give a clear light goldenliquid. The liquid was purified by flash chromatography and eluted with3:1 hexane/ethyl acetate containing 5% acetic acid. The desiredfractions were combined and evaporated to givebutyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3, R=n-butyl,R1=H) (2.9 g, 40%) as a clear and colorless oil. Rfo.12 (3:1, Hex./EtOAc5% AcOH).

[0821]¹H NMR (d6-DMSO): 7.3 ppm (m, 10), 5.0 ppm (s,4H), 2.7 ppm (m, 1H)2.3 ppm (y, 2H), 1.8 ppm (m, 2H), 1.3 ppm (m, 4H), 0.8 ppm (t, 3H)

2-[(Butylhydroxyphosphinyl)methyl]pentanedioic acid

[0822] Butyl(2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (2.9 g, 6.5mmol) in 30 mL of water containing 0.32 g 10% Pd/C was hydrogenated on aParr hydrogenator at 40 psi for 4.5 hours. The mixture was filteredthrough a pad of Celite and evaporated under high vacuum to give2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=n-butyl) (0.75g, 43%) as a clear and colorless viscous oil.

[0823]¹H NMR (D₂O): 2.4 ppm (m, 1H), 2.1 ppm (t, 2H), 1.9 ppm (m, 1H),1.6 ppm (m, 3H), 1.4 ppm (m, 2H), 1.1 ppm (m, 4H), 0.6 ppm (t, 3H)

[0824] Elemental Analysis Calculated C₁₀H₁₉O₆P. 0.5 H₂O: C 43.64, H7.32: Found C 43.25, H 7.12

Example 3 Preparation of 2-[(benzylhydroxyphosphinyl)methyl]pentanedioicacid

[0825] Scheme IV R=CH2Ph, R1=H

[0826] Benzylphosphinic Acid

[0827] Diethylchlorophosphite (25 g, 0.16 mol) in 100 mL of dry diethylether was cooled to 0° C. under an atmosphere of nitrogen.Denzylmagnesium chloride (80 mL, 0.16 mol, 2.0 M solution in Et₂O) wasadded dropwise over two hours while maintaining a temperature below 10°C. A thick white slurry formed and stirring was continued at roomtemperature for 1 hour. The mixture was filtered under a nitrogenatmosphere and the filtrate evaporated under reduced pressure to give aclear and colorless liquid. The liquid was stirred as 15 mL of water wasadded followed by 0.5 ml concentrated hydrochloric acid. An exothermicreaction was observed and stirring was continued for an additional 30minutes followed by extraction with ethyl acetate. The organics werecombined, washed with brine, dried (MgsO₄) and evaporated, The clearlight golden liquid was added to sodium hydroxide (50 mL, 2.0 M NaOH),stirred for one hour and washed with diethyl ether. The aqueous layerwas acidified to pH 1.0 with concentrated hydrochloric acid andextracted with ethyl acetate. The organics were combined, dried (MgSO₄)and evaporated to give benzylphosphinic acid (1, R=CH2Ph, R1+H) (8 g,32%) as a clear light golden oil.

[0828]¹H NMR (d6-DMSO): 7.3 ppm (m, 5H), 6.9 ppm (d, 1H), 3.1 ppm (d,2H)

Benzyl[2,4-di(benzyloxyxcarbonyl)butyl]phosphinic acid

[0829] Benzylphosphinic acid (2.3 g, 15 mmol) in 150 mL of drydichloromethane was cooled to 0° C. under a nitrogen atmosphere.Triethylamine (6.5 g, 65 mmol) was added followed by trimethylsilylchloride (5.8 g, 54 mmol) while the reaction temperature was maintainedat 0° C. After 30 minutes dibenzyl 2-methylenepentanediote (2) in 20 mLof dichloromethane was added over 5 minutes. The reaction mixture wasleft to warm to room temperature and stirred overnight. The clearsolution was cooled to 0° C. and quenched with 5% hydrochloric acid andwith brine, dried (MgSO₄) and evaporated to give a clear yellow liquid.Purification by flash chromatography and elution with 1:1 hexane/ethylacetate containing 10% acetic acid yielded 2.0 g (28%) ofbenzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (3, R=CH2Ph, R1+H)as a clear light yellow oil. Rf 0.37 (1:1 Hex./EtOAc, 10% AcOH).

[0830]¹H NMR (d6-DMSO): 7.2 ppm(m,15H), 5.0 ppm(s,4H),3.0 (d,2H),2.8ppm(m,1H),2.3 ppm(t,2H), 1.9 ppm(m,2H), 1.7 ppm(t,1H)

2-[(Benzylhydroxyphosphinyl)methyl]entanedioic acid

[0831] Benzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid(0.5 g, 1.0mmol) in 20 mL of water containing 120 mg of 10% Pd/C was hydrogenatedon a Part hydrogenator at 40 psi for 6 hours. Filtration through aCelite pad followed by evaporation on high vacuum gave 0.17 g (57%) of2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid(4, R=CH2Ph) as awhite solid.

[0832] 1H NMR (D₂O): 7.1 ppm(m,5H), 2.9 ppm(d,2H), 2.4 ppm(m,1H), 2.1ppm(t,2H), 1.8 ppm(m,1H), 1.6 ppm(m,3H)

[0833] Elemental Analysis, Calculated C₁₃H₁₇O₆P: C_(52.00)H5.71: Found:C51.48H5.70

Example 4 Preparation of2-(phenylethylhydroxyphosphinyl)methyl]pentanedioic acid

[0834] Scheme IV R=Ch2CH2Ph, R1=H

[0835] Phenethylphosphinic Acid

[0836] Diethylchlorophosphite (15.6 g, 0.l mol) in 100 mL of dry diethylether was cooled to 50° C. under an atmosphere of nitrogen.Phenethylmagnesium chloride (100 mL, 0.1 mol, 1.0 M in THF) was addeddropwise over 2 hours while maintaining a temperature between 0-10° C. Athick white slurry formed and stirred at room temperature overnight. Themixture was filtered under a nitrogen atmosphere and the filtrateevaporated under reduced pressure to give a clear and colorless liquid.The liquid was stirred as 15 mL of water was added followed by 0.5 mL ofconcentrated hydrlochloric acid. An exothermic reaction was observed andstirring continued for 15 minutes followed by extraction with ethylacetate. The organics were combined, washed with brine, dried (MgSO₄)and evaporated. The clear liquid was brought up in sodium hydroxide (40mL, 2.0 M NaCH), stirred for 1 hour and washed once with diethyl ether.The aqueous layer was acidified to pH 1.0 with concentrated hydrochloricacid and extracted with ethyl acetate. The organics were combined, dried(MgSO₄) and evaporated to give phenethylphosphinic acid (1, R=CH2CH2Ph,R1=H) (9.8 g, 58%) as a clear light yellow oil.

[0837]¹H NMR (d6-DMSO):7.2 ppm (m,5H), 6.9 ppm (d,1H), 2.8 ppm (m,2H),1.9 ppm (m,2H)

2,4-Di(benzyloxycarbonyl)butyl(phenethyl)phosphinic acid

[0838] Phenethylphosphinic acid (1.0 g, 5.9 mmol) in 50 mL of drydichloromethane was cooled to −5° C. under a nitrogen atmosphere.Triethylamine (2.3 g, 23 mmol) was added followed by trimethylsilylchloride 2.2 g, 21 mmol) while the reaction temperature was maintainedat 0° C. After 10 minutes dibenzyl 2-methylenepentanedioate (2) in 10 mLof dichloromethane was added over 10 minutes. The reaction mixture wasleft to warm to room temperature and stirred overnight. The clearsolution was cooled to 0° C. and quenched with 5% hydrochloric acidfollowed by removal of the organic layer. The organic layer was washedwith brine, dried (MgSO4) and evaporated to give a clear light goldenliquid. Purification by flash chromatography and elution with 1:1Hexane/EtOAc containing 5% AcOH resulted in 1.2 g (41%) of2,4-di(benzyloxycarbonyl)butyl(phenethyl)phosphinic acid(3, R=CH2CH2Ph,R1=H) as a clear and colorless oil.

[0839]¹H NMR (d6-DMSO): 7.2 ppm(m,15H),5.0 ppm (s,4H) 3.3 ppm (m,1H) 2.8ppm(m,4H), 2.3 ppm(m,2), 1.8 ppm(m,4H)

2,4-[(Phenethylhydroxyphosphinyl)methyl]pentanedioic acid

[0840] 2,4-Di(benzyloxycarbonyl)butyl(phenethyl)phosphinic acid(1.1 g,2.2 mmol) in 20 mL of water containing 120 mg of 10% Pd/C washydrogenated on a Parr hydrogenator at 40 psi overnight. Filtrationthrough a Celite pad followed by evaporation on high vacuum gave 0.8 g(114%) of 2-[(phenethylhydroxyphosphinyl)methyl]pentanedioic acid(4,R=CH2CH2Ph) as a white solid.

[0841]¹H NMR(D₂O): 7.2 ppm (m,5H), 2.7 ppm (m,2H), 2.5 ppm (m,1H) 2.3ppm (t,2H), 1.9 ppm (m,6H), 1.5 ppm (t,1H)

[0842] Elemental Analysis: Calculated C₁₄H₁₉O₆P 0.75H₂O, 0.5 AcOH: C50.35 H 6.34 Found: C 50.26 H 5.78

Example 5 Preparation of2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid

[0843] Scheme IV R=CH2CH2CH2Ph, R1=H

[0844] 3-Phenylpropylphosphinic Acid

[0845] Magnesium turnings (2.44 g, 0.10 mol) in 20 mL of dry diethylether under an atmosphere of nitrogen was added several iodine crystals.Phenylpropyl bromide (20.0 g, 0.10 mol) in 80 mL of diethyl ether wasplaced in a dropping funnel. Approximately 10 mL of the bromide solutionwas added to the magnesium turnings and stirring was initiated. Afterseveral minutes the iodine was consumed and additional phenylpropylbromide was added while maintaining a temperature of 35° C. Onceadditional was complete (1.5 hours) the mixture was sealed and stored at5° C.

[0846] Diethylchlorophosphite (15.7 g, 0.1 mol) in 50 mL of dry diethylether was cooled to 5° C. under an atmosphere of nitrogen.Phenylpropylmagnesium bromide (100 mL, 0.1 mol. 1.0 M solution of inEt₂O) was added dropwise over 2 hours while maintaining a temperaturebetween 0-10° C. A thick white slurry formed and was stirred anadditional 30 minutes. The mixture was filtered under a nitrogenatmosphere and the filtrate evaporated under reduced pressure to give aclear and colorless liquid. To the liquid was added 20 mL of waterfollowed by 0.5 ml of concentrated hydrlochloric acid. An exothermicreaction was observed and stirring continued for 20 minutes followed byextraction with ethyl acetate. The organics were combined, washed withbrine, dried (MgSO₄) and evaporated. To the clear liquid was addedsodium hydroxide (40 mL, 2.0 M NaOH), the resulting solution stirred for1 hour and then washed with diethyl ether. The aqueous layer wasacidified to pH 1.0 with concentrated hydrochloric acid and extractedtwice with ethyl acetate. The organics were combined, dried (MgSO₄) andevaporated to give 3-phenylpropylphosphinic acid (1, R=CH2CH2CH2Ph,R1=H) (9.8 g, 53%) as a clear and colorless oil.

[0847]¹H NMR (d6-DMSO): 7.2 ppm (m,5H), 6.9 ppm (d,1H), 2.6 ppm (t,2H).1.7 ppm (m,2H), 1.6 ppm (m,2H)

2,4-Di(benzyloxycarbonyl)butyl(3-phenylpropyl)phosphinic acid

[0848] 3-phenylpropylphosphinic acid(1.0 g, 5.4 mmol) in 50 mL of drydichloromethane was cooled to −5° C. under a nitrogen atmosphere.Triethylamine (2.2 g, 22 mmol) was added followed by trimethylsilylchloride (2.1 g, 19 mmol) while the reaction temperature was maintainedat 0° C. After 10 minutes dibenzyl 2-methylenepantanedioate (2) in 10 mLof dichloromethane was added over 10 minutes. The reaction mixture waswarmed to room temperature and stirred overnight. The clear solution wascooled to 0° C. and quenched with 5% hydrochloric acid followed byremoval of the organic layer. The organic layer was washed with brine,dried (MgSO₄) and evaporated to give a clear yellow liquid. Purificationby flash chromatography and elution with 4:1 hexane/ethyl acetatecontaining 5% acetic acid resulted in 1.5 g (56%) of2,4-di(benzyloxycarbonyl)butyl(3-phenylpropyl)phosphinic acid(3,R=CH2CH2CH2Ph, R1=H) as a clear light yellow oil. Rf 0.58 (1:1Hex./EtOAc, 5% AcOH);

[0849]¹H NMR (d6-DMSO): 7.2 ppm (m,15H), 5.0 ppm (s,4H), 2.7 ppm (m,1H), 2.5 ppm (m,5H), 2.2 ppm (m,2H),1.8 ppm(m,3H), 1.6 ppm (m,2H)

[0850] Elemental Analysis: Calculated C₂₉H₃₃O₆P 1.3H₂O: C 65.48 H 6.75Found: C 65.24 H 6.39

2-[(3-Phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid

[0851] 2,4-Di(benzyloxycarbonyl)butyl(3-phenylpropyl)phosphinic acid(15) (1.4 g, 2.8 mmol) in 20 mL of water containing 150 mg of 10% Pd/Cwas hydrogenated on a Parr hydrogenator at 40 psi overnight. Filtrationthrough a Celite pad followed by evaporation on high vacuum gave 0.8 g(89%) of 2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid(4, R=CH2CH2CH2Ph) as a light yellow viscous oil).

[0852]¹H NMR (D2O): 7.4 ppm (m,5H), 2.7 ppm (m,3H), 2.4 ppm (t,3H), 1.8ppm (m,7H);

[0853] Elemental Analysis: Calculated C₁₅H₂₁O₆P 0.75 H₂O, 0.75 AcOH:C_(51.23) H 6.64 Found: C_(50.85) H 6.02

Example 6 Preparation of2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid

[0854] Scheme V, Compound 5

[0855] Hexamethyldisilazane (21.1 mL, 100 mmol) was added to vigorouslystirred ammonium phosphinate (8.30 g, 100 mmol), and the resultingsuspension was stirred at 105 C. for 2 h. A solution of 4-methylbenzylbromide (5.00 g, 27.0 mmol) was then dropwise added to the suspension at0° C. The mixture was Stirred at rt for 19 h. The reaction mixture wasthen diluted with dichloromethane (50 mL) and washed with 1 N HCl (50mL). The organic layer was separated, dried over Na₂SO₄, andconcentrated to give 4.72 g of a white solid. This was dissolved indichloromethane (50 mL) and benzyl alcohol (3.24 g, 30 mmol) was addedto the solution. 1,3-Dicyclohexylcarbodiimide (DCC) (6.19 g, 30 mmol)was then added to the solution at 0° C., and the suspension was stirredat rt for 14 h. The solvent was removed under reduced pressure and theresidue was suspended in EtOAc. The resulting suspension was filteredand the filtrate was concentrated. The residue was purified by silicagel chromatography (hexanes: EtOAc, 4:1 to 1:1) to give 2.40 g of4-methylbenzyl-O-benzylphosphinic acid (2, R=4-methylbenzyl) as a whitesolid (34% yield): Rf 0.42 (EtOAc); ¹H NMR (DMSO-d₆) delta 2.30 (s, 3H), 3.29 (d, J=16.6 Hz, 2 H), 5.2 (m, 2 H), 7.0 (d, J=543 Hz, 1 H),7.1-7.2 (m, 4 H), 7.3-7.4 (m, 5 H)

[0856] To a solution of 4-methylbenzyl-O-benzylphosphinic acid (2,R=4-methylbenzyl) (2.16 g, 8.3 mmol) in THF (15 mL) was added sodiumhydride (0.10 g, 60% dispersion in oil) followed by dibenzyl2-methylenepentanedioate at 0 C., and the mixture was stirred at rt for4 h. The reaction mixture was then diluted with EtOAc (50 mL) and pouredinto 1N HCl (50 mL) The organic layer was separated, dried over Na₂SO₄,and concentrated. This material was purified by silica gelchromatography (hexanes: EtOAc, 4:1 to 1:1) to give 3.41 g of2,4-di(benzyloxycarbonyl)butyl(4-methylbenzyl)-O-benzylphosphinic acid(4, R=4-methylbenzyl) as colorless oil (70% yield): Rf 0.61 (EtOAc); ¹HNMR (CDCl₃) delta 1.6-1.8 (m, 1 H), 1.9-2.0 (m, 2 H), 2.1-2.4 (m, 6 H),2.7-2.9 (m, 1 H), 3.05 (dd, J=9.0, 16.8 Hz, 2 H), 4.8-5.1 (m, 6 H),7.0-7.1 (m, 4 H), 7.2-7.4 (m, 15 H)

[0857] To a solution of2,4-di(benzyloxycarbonyl)butyl(4-methylbenzyl)-O-benzylphosphinic acid(0.70 g, 1.2 mmol) in ethanol (30 mL) was added Pd/C (5%, 0.10 g) andthe suspension was shaken under hydrogen (50 psi) for 18 h. Thesuspension was then filtered through a pad of Celite and concentratedunder reduced pressure. The resulting residue was dissolved in distilledwater (5 mL), passed through a column of AG 50W-X8 resin (H⁺ form), andlyophilized to give 0.21 g of2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid (5,R=4-methylbenzyl) as a white solid (55% yield): Rf 0.62 (i-PrOH:H₂O,7:3); ¹H NMR (D₂O) delta 1.7-1.9 (m, 3 H), 2.0-2.2 (m, 1 H), 2.33 (dt,J=1.7 Hz, 7.4 Hz, 2 H), 2.55-2.70 (m, 1 H), 3.12 (d, J=16.5 Hz, 2 H),7.0-7.1 (m, 2 H), 7.2-7.3 (m, 2 H). Anal. Calcd for C₁₃H₁₇O₆P*0.30H₂O:C,52.60; H, 6.18. Found: C, 52.60; H, 6.28.

Example 7 Preparation of2-[[(4-Fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid(R=4-fluorobenzyl)

[0858] Scheme V, Prepared as Described in the Above Example WhereR=methylbenzyl

[0859] Rf 0.64 (i-PrOH:H₂O, 7:3); ¹H NMR (D₂O) delta 1.7-1.9 (m, 3 H),2.0-2.2 (m, 1 H), 2.3-2.4 (m, 2 H), 2.55-2.70 (m, 1 H), 3.12 (d, J=16.5Hz, 2 H), 7.0-7.1 (m, 2 H), 7.2-7.3 (m, 2 H). Anal. Calcd forC₁₃H₁₆FO₆P*0.25H₂O:C, 48.38; H, 5.15. Found: C, 48.38; H, 5.15.

Example 8 Preparation of2-[[(4-Methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid(R=4-methoxybenzyl)

[0860] Scheme V, Prepared as Described in the Above Example WhereR=methylbenzyl

[0861] Rf 0.56 (i-PrOH:H₂O, 7:3); ¹H NMR (D₂O) delta 1.8-1.9 (m, 3 H),2.0-2.2 (m, 1 H), 2.3-2.4 (m, 2 H), 2.55-2.70 (m, 1 H), 3.16 (d, J=16.7Hz, 2 H), 3.81 (s, 3 H), 6.98 (d, J=8.7 Hz, 2 H), 7.25 (d, J=8.7 Hz, 2H). Anal. Calcd for C₁₄H₁₉O₇P*0.30H₂O:C,50.09; H, 5.89. Found: C, 49.98;H, 5.80.

Example 9 Preparation of2-[[(2-Fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid(R=2-fluorobenzyl)

[0862] Scheme V, Prepared as Described in the Above Example WhereR=methylbenzyl

[0863] Rf 0.67 (i-PrOH:H₂O, 7:3); ¹H NMR (D₂O) delta 1.8-1.9 (m, 3 H),2.0-2.2 (m, 1 H), 2.3-2.4 (m, 2 H), 2.55-2.70 (m, 1 H), 3.28 (d, J=16.6Hz, 2 H), 7.1-7.5 (m, 4 H). Anal. Calcd for C₁₃H₁₆FO₆P*0.10H₂O:C,48.79;H, 5.10. Found: C, 48.84; H, 5.14.

Example 10 Preparation of2-[[(Pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid(R=pentafluorobenzyl)

[0864] Scheme V, Prepared as Described in the Above Example WhereR=methylbenzyl

[0865] Rf 0.69 (i-PrOH:H₂O, 7:3); ¹H NMR (D₂O) delta 1.8-2.0 (m, 3 H),2.1-2.3 (m, 1 H), 2.3-2.5 (m, 2 H), 2.7-2.9 (m, 1 H), 3.29 (d, J=15.4Hz, 2 H), Anal. Calcd for C₁₃H₁₂F₅O₆P*0.45H₂O:C,39.20; H, 3.26. Found:C, 39.17; H, 3.28.

Example 11 Preparation of2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid

[0866] Scheme VI, Compound 9

[0867] 2,4-Di(benzyloxycarbonyl)butylphosphinic acid (6) Dry phosphinicacid (100 g, 1.52 mol) was dissolved in 100 ml of chloroform and treatedwith triethylamine (155 g, 1.52 mol). The mixture was evaporated andtransferred to a three liter flask, containing 750 mL of chloroform. Thesolution was stirred by means of a mechanical stirrer and the flaskcooled to 0° C. The clear solution was treated with triethylamine (277g, 2.72 mol) followed by trimethylsilyl chloride (281 g, 2.58 mol). Onceaddition of trimethylsilyl chloride was complete dibenzyl2-methylenepentanedioate (2) in 150 mL of chloroform was added dropwiseover 20 minutes. The low temperature bath was removed and the mixturewarmed to room temperature. After 6 hours the thick slurry was filteredand the filtrate cooled to 0C. The filtrate was then quenched with 5%hydrochloric acid and the organic layer removed. The aqueous layer wasextracted with chloroform, the organics combined, dried (MgSO₄) andevaporated under reduced pressure to give 55 g of2,4-di(benzyloxycarbonyl)butylphosphinic acid (6) as a light yellowliquid. The liquid was purified by flash chromatography and eluted using3:1 hexanes/ethyl acetate containing 5% trifluoroacetic acid to give 40g (7%) of the desired product. Rf0.28(3:1 Hex./EtOAc 5% TFA);

[0868]¹H NMR (CDCl₃): 7.3 ppm (m, 10H), 7.2 ppm (d, 1H), 5.12 ppm (s,2H), 2.9 ppm (m, 1H), 2.4 ppm (t, 2H), 2.2 ppm (m, 1H), 2.0 ppm (m, 3H)

2,4-Di(benzyloxycarbonyl)butylbenzylhosihinic acid (7)

[0869] To a solution of 2,4-di-(benzyloxycarbonyl)butyl phosphinic acid(6) (19.3 g, 49.4 mmol) in tetrahydrofuran was added benzyl alcohol (5.3g, 49.3 mmol) and dimethylamino in tetrahydrofuran was added benzylalcohol (5.3 g, 49.3 mmol) and dimethylamino pyridine (0.5 g).Dicylcohexylcarbodiimide (DCC, 12 g, 58 mmol) was added and a whiteprecipitate formed. After 30 minutes the white suspension was filteredand the filtrate evaporated under reduced pressure. The clear andcolorless oil was purified by flash chromatography and eluted with 1:1Hex./EtOAc to give 2,4-di(benzyloxycarbonyl)butylbenzylphosphinic acid(7) (11.5 g, 47%) as a clear and colorless oil. Rf. 0.16 (1:1Hex./EtOAc);

[0870]¹H NMR (CDCl₃): 7.3 ppm (m,15H), 7.2 ppm (d, 1H), 5.0 ppm (m,6H),2.9 ppm (m,1H), 2.2 ppm (m,3H), 1.9 ppm (m,3H)

2,4-Di(benzyloxycarbonyl)butyl[hydroxy(phenyl)methyl]benzylphosohinicacid (8)

[0871] 2,4-Di(benzyloxycarbonyl)butylbenzylphosphinic acid (7) in 5 mLof dry THF was added dropwise to a stirring cooled (0° C.) mixture ofsodium hydride (0.09 g, 2.3 mmol) in 15 mL of THF. After 15 minutesbenzaldehyde (0.23 g, 2.3 mmol) was added via syringe while maintaininga temperature of 0° C. After 30 minutes the mixture was quenched withwater and extracted with two portions of dichloromethane. The organicswere combined and evaporated to give a clear colorless oil. The oil waschromatographed on silica and eluted with a 1:1 Hex./EtOAc solventsystem. The desired fractions were collected and evaporated to give 0.4g (33%) of2,4-di(benzyloxycarbonyl)butyl[hydroxy(phenyl)methyl]benzylphosphinicacid (6) as a clear and colorless oil. RfO.18(1:1 Hex./EtOAc);

[0872]¹H NMR (CDCl₃): 7.3 ppm (m,20H), 5.2 ppm (m,1H), 4.9 ppm (m,6H),2.8 ppm (dm,1H), 2.2 ppm (m,3H), 1.9 ppm (m,3H)

2-([Hydroxy(phenyl)methyl]hydroxyphosphinylmethyl)pentanedioic acid(9)

[0873]2,4-Di(benzyloxycarbonyl)butyl[hydroxy(phenyl)methyl]benzylphosphinicacid(6) (0.37 g, 0.6 mmol) in 25 mL of water containing 0.10 g of 10%Pd/C was hydrogenated at 40 psi for 6 hours. The mixture was filteredthrough a pad of Celite and lyophilized to give2-([hydroxy(phenyl)methyl]hydroxyphosphinylmethyl)pentanedioic acid (9)(0.14 g, 70%) as a white solid.

[0874]¹H NMR (D2O): 7.4 ppm (m,5H), 5.0 ppm (d,1H), 2.7 ppm (m,1H), 2.4ppm (m,2H), 2.2 ppm (m,1H),1.9 ppm(m,3H)

[0875] Element Analysis: Calculated C₁₃H₁₇C₇P. 0.6H₂O:C 47.74 H 5.61Found: C 47.73 H 5.68

Example 12 Preparation of Dibenzyl 2-Methyleneoentanedioate

[0876] Scheme III

[0877] Benzyl acrylate (500 g, 3 mol) was heated to 100° C. under anatmosphere of nitrogen. The heating was stopped and HMPT (10 g, 61 mmol)was added dropwise while maintaining an internal temperature of 135-145°C. Once addition was complete the mixture was cooled to room temperatureand a slurry of silica with 5:1 Hex/EtOAc was added. The slurry was thentransferred to a column containing a plug of dry silica. The column wasthen washed with 1:1 Hex/EtOAc and the solvent was collected andevaporated. The clear yellow liquid was distilled under high vacuum (200μHg) to give an initial fraction of 8 g distilling at 45° C. and thenthe desired product at 180-185° C. (212 g, 42%) as a clear and colorlessliquid.

[0878]¹H-NMR (CDCl₃) 7.3 ppm (s, 10H); 6.2 ppm (s, 1H); 5.5 ppm (s, 1H);5.2 ppm (s, 2H); 5.1 ppm (s,2H); 2.6 ppm (m, 4H).

Example 13 Preparation of Dibenzyl2-[[Bis(benzyloxy)phosphoryl]methyl]-pentanedioate

[0879] Scheme III

[0880] Dibenzyl phosphite (9.5 g, 36 mmol) in 350 ml of dichloromethanewas cooled to 0° C. To this stirring solution was added trimethylaluminum (18.2 ml, 2.0M solution in hexane, 36.4 mmol). After 30 minutes1 (6.0 g, 37 mmol) in 90 ml of dichloromethane was added dropwise over10 minutes. The clear and colorless solution was then warmed to roomtemperature and left to stir overnight. The mixture was then quenched bythe slow addition of 5% HCl. After stirring an additional 1.5 hours thelower organic layer was removed and the aqueous layer extracted oncewith 100 ml of dichloromethane. The organics were combined, dried(MgSO₄), and evaporated to give a clear light golden liquid. The liquidwas chromatographed on silica gel (4 cm*30 cm) and eluted with agradient (4:1-1:1) solvent system (Hexane/EtOAc). The fractionscontaining the desired product were combined and evaporated to yield 2(7.1 g, 42%) as a clear and colorless liquid. The liquid was thendistilled on a Kughleror apparatus at 0.5 mm Hg and 195-200° C. Thedistillate was discarded and the remaining light golden oil waschromatographed on silica gel (1:1, Hex./EtOAc) to give 2.9 g of 2 as aclear and colorless oil. TLC R_(f) 0.5 (1:1, Hex./EtOAc).

[0881] 1H-NMR (CDCl₃) 7.1-7.4 (m, 20H); 5.05 (s, 2H); 4.8-5.03 (m, 6H);2.8 (1H) 2.22-2.40 (m, 3H); 1.80-2.02 (m, 3H).

Example 14 Preparation of 2-(Phosphonomethyl)pentanedioic Acid

[0882] Scheme III

[0883] The benzyl pentanedioate (2.9 g, 4.9 mmol) was added to a mixtureof 20 ml of methanol containing 0.29 g (6 mol %) of 10% Pd/C. Thismixture was hydrogenated on a Parr hydrogenator at 40 psi for 24 hours,filtered and evaporated to give 3(1.0 g, 90%) as a clear slightly goldenviscous oil.

[0884] 1H-NMR (D₂O) 2.6-2.78(m, 1H); 2.25-2.40(m, 2H); 1.75-2.15(m, 4H)

Example 15

[0885] A patient is diagnosed with adenocarcinoma of the prostate. Thepatient may then be administered a NAALADase inhibitor, such as setforth in examples 1 through 3, by direct injection into the tumor. Afterthis initial treatment, the patient may be optionally administered thesame or different NAALADase inhibitor by intermittent or continuousadministration by subdural pump. It would be expected that no furtheroccurrences of the adenocarcinoma would develop.

Example 16

[0886] A patient is diagnosed with adenocarcinoma of the prostate. Thepatient may then be administered a NAALADase inhibitor, such as setforth in examples 1 through 3, by direct injection into the tumor. Afterthis initial treatment, the patient may be optionally administered thesame or different NAALADase inhibitor by intermittent or continuousadministration by implantation of a biocompatible, polymeric matrixdelivery system. It would be expected that no further occurrences of theadenocarcinoma would develop.

Example 17

[0887] A patient is diagnosed with benign prostatic hyperplasia. Thepatient may then be administered a NAALADase inhibitor, such as setforth in examples 1 through 3, by direct injection into the tumor. Afterthis initial treatment, the patient may be optionally administered thesame or different NAALADase inhibitor by intermittent or continuousadministration by injection, subdural pump, or polymeric matrix implant.It would be expected that the benign prostatic hyperplastic cells do notdevelop into carcinoma.

Example 18

[0888] A patient is diagnosed with adenocarcinoma of the prostate. Theadenocarcinoma appears not to have metastasized. The adenocarcinomawould be removed by surgery. After post-operative recovery, the patientwould be locally administered NAALADase inhibitor by intermittent orcontinuous administration by injection, subdural pump or by polymericmatrix implant. It would expected that no further occurrences of thecarcinoma would develop.

Example 19

[0889] A patient is diagnosed with metastatic adenocarcinoma of theprostate. The adenocarcinoma appears to have metastasized, but surgerystill is indicated as an effective treatment modality. Tumor tissuewould be removed by surgery. The patient would be locally administered aNAALADase inhibitor such as described herein from the time,approximately, of the initial diagnosis and would continue aftersurgery. After post-operative recovery, the patient would be maintainedat this level of NAALADase inhibitor by a regimen of periodic localadministration. The patient would be monitored carefully for intolerableadverse side-effects of NAALADase inhibitor administration. It would beexpected that no further tumors develop. If some of the original, smalltumorous masses are detected after surgery, they would be expected tonot grow in size.

Example 20

[0890] A patient is diagnosed with ACTH-producing tumors. The patientmay then be administered a NAALADase inhibitor, such as set forth inexamples 1 through 3, by direct injection into the tumor. After thisinitial treatment, the patient may be optionally administered the sameor different NAALADase inhibitor by direct injection, subdural pump, orimplantation of a biocompatible, polymeric matrix delivery system. Itwould be expected that tumor growth or tumor cell growth would beprevented or inhibited and that no further occurrences of theACTH-producing tumor would develop.

Example 21

[0891] A treatment such as that described in Example 9 wherein thepatient is diagnosed with acute lymphocytic leukemia.

Example 22

[0892] A treatment such as that described in Example 9 wherein thepatient is diagnosed with acute non-lymphocytic leukemia.

Example 23

[0893] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic cancer of theadrenal cortex.

Example 24

[0894] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic bladder cancer.

Example 25

[0895] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic brain cancer.

Example 26

[0896] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic breast cancer.

Example 27

[0897] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic cervical cancer.

Example 28

[0898] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic chroniclymphocytic leukemia.

Example 29

[0899] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic chronicmyelocytic leukemia.

Example 30

[0900] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic colorectalcancer.

Example 31

[0901] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic cutaneous T-celllymphoma.

Example 32

[0902] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic endometrialcancer.

Example 33

[0903] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic esophagealcancer.

Example 34

[0904] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic Ewing's sarcoma.

Example 35

[0905] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic gallbladdercancer.

Example 36

[0906] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic hairy cellleukemia.

Example 37

[0907] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic head and neckcancer.

Example 38

[0908] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic Hodgkin'slymphoma.

Example 39

[0909] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic Kaposi's sarcoma.

Example 40

[0910] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic kidney cancer.

Example 41

[0911] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic liver cancer.

Example 42

[0912] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic lung cancer(small cell and/or non-small cell)

Example 43

[0913] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic malignantperitoneal effusion.

Example 44

[0914] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic malignant pleuraleffusion.

Example 45

[0915] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic melanoma.

Example 46

[0916] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic mesothelioma.

Example 47

[0917] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic multiple myeloma.

Example 48

[0918] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic neuroblastoma.

Example 49

[0919] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic non-Hodgkin'slymphoma.

Example 50

[0920] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic osteosarcoma.

Example 51

[0921] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic ovarian cancer(and/or germ cell ovarian cancer).

Example 52

[0922] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic pancreaticcancer.

Example 53

[0923] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic penis cancer.

Example 54

[0924] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic retinoblastoma.

Example 55

[0925] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic skin cancer.

Example 56

[0926] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic soft-tissuesarcoma.

Example 57

[0927] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic squamous cellcarcinoma.

Example 58

[0928] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic stomach cancer.

Example 59

[0929] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic testicularcancer.

Example 60

[0930] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic thyroid cancer.

Example 61

[0931] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic trophoblasticneoplasm.

Example 62

[0932] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic uterine cancer.

Example 63

[0933] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic vaginal cancer.

Example 64

[0934] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic cancer of thevulva.

Example 65

[0935] A treatment such as that described in Example 9 wherein thepatient is diagnosed with metastatic or non-metastatic Wilm's tumor.

[0936] The invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention and all suchmodification are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A method of treating cancer in an animal whichcomprises: administering to an animal suffering from a cancer aneffective amount of a NAALADase inhibitor.
 2. The method of claim 1wherein the NAALADase inhibitor is selected from the group consistingof: a glutamate-derived hydroxyphosphinyl derivative compound; an acidicpeptide analog; a conformationally restricted glutamate mimic; andmixtures thereof.
 3. The method of claim 2 wherein the acidic peptideanalog is selected from the group consisting of: Asp-Glu, Glu-Glu,Gly-Glu, gamma-Glu-Glu, and Glu-Glu-Glu.
 4. The method of claim 2wherein the conformationally restricted glutamate mimic is selected fromthe group consisting of beta-NAAG and quisqualic acid.
 5. The method ofclaim 2 wherein the NAALADase inhibitor is a glutamate-derivedhydroxyphosphinyl derivative compound.
 6. The method of claim 1 whereinthe NAALADase inhibitor is administered in combination with anadditional therapeutic agent selected from the group consisting of:therapeutic hormones, chemotherapeutic hormones, anti-angiogenesisagents, radiolabelled compounds, and mixtures thereof.
 7. The method ofclaim 1 wherein the cancer is selected from the group consisting of:ACTH-producing tumors, acute lymphocytic leukemia, acute nonlymphocyticleukemia, cancer of the adrenal cortex, bladder cancer, brain cancer,breast cancer, cervical cancer, chronic lymphocytic leukemia, chronicmyelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma,endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladdercancer, hairy cell leukemia, head & neck cancer, Hodgkin's lymphoma,Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer, lung cancer(small and/or non-small cell), malignant peritoneal effusion, malignantpleural effusion, melanoma, mesothelioma, multiple myeloma,neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovary(germ cell) cancer, pancreatic cancer, penis cancer, prostate cancer,retinoblastoma, skin cancer, soft tissue sarcoma, squamous cellcarcinomas, stomach cancer, testicular cancer, thyroid cancer,trophoblastic neoplasms, cancer of the uterus, vaginal cancer, cancer ofthe vulva, and Wilm's tumor.
 8. The method of claim 1 wherein the canceris prostatic adenocarcinoma.
 9. The method of claim 1 wherein the canceris selected from the group consisting of: brain cancer, cancer of theadrenal cortex, kidney cancer, and testicular cancer.
 10. The method ofclaim 1 wherein the NAALADase inhibitor comprises a compound having thefollowing formula:

wherein R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; X is CH₂, O, or NR₁, where R₁ is defined above;and R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid, wherein said alkyl,alkenyl, cycloalkyl, cycloalkenyl or aryl groups may be optionallysubstituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C⁷cycloalkenyl, C₁-C₄ alkyl, C₁-C₄ alkenyl, halo, hydroxy, carboxy, nitro,trifluoromethyl, C₁-C₆ straight or branched chain alkyl or alkenyl,C₁-C₄ alkoxy, C₁-C₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar₁, andwhere Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl,tetrahydrofuranyl, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-, or4-pyridyl, or phenyl, having one to five substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxy, carboxy, nitro, trifluoromethyl, C₁-C₆ straight or branchedalkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; or pharmaceutically acceptable salts, hydrates, or mixturesthereof.
 11. The method of claim 10 wherein R₁ and R₂ are straight orbranched aliphatic groups or carbocyclic groups and X is CH₂.
 12. Themethod of claim 11 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[[methylhydroxyphosphinyl]methyl]pentanedioicacid; 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[benzylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-(phosphonomethyl)pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;3-(methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(cyclohexylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((cyclohexyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylpropylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylbutylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylprop-2-enylhydroxyphosphinyl)-2-phenylpropanoic acid;2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid;2-[(methylhydroxyphosphinyl)methyl]hexanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]hexanedioic acid;2-[(methylhydroxyphosphinyl)methyl]heptanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]heptanedioic acid;2-[(methylhydroxyphosphinyl)methyl]octanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]octanedioic acid;2-[(methylhydroxyphosphinyl)methyl]nonanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]nonanedioic acid;2-[(methylhydroxyphosphinyl)methyl]decanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]decanedioic acid;3-(benzylhydroxyphosphinyl)-2-methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-propypropanoic acid;3-(benzylhydroxyphosphinyl)-2-butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-cyclohexyipropanoic acid;3-(benzylhydroxyphosphinyl)-2-(cyclohexyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-benzylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylethyipropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylbutylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2,3,4-trimethoxyphenyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)methylpropancic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylprop-2-enylpropanoic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;3-[(2-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(tetrahydrofuranyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(tetrahydrofuranyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(tetrahydrofuranyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propylpropanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 13. Themethod of claim 11 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[(benzylhydroxyphosphinyl)methyl]pentanedioicacid; 2-[(phenylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[((hydroy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-(phosphonomethyl)pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 14. Themethod of claim 10 wherein R₁ and R₂ are straight or branched aliphaticgroups or carbocyclic groups and X is oxygen.
 15. The method of claim 14wherein the NAALADase inhibitor is selected from the group consistingof: 2-[[methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[butylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phnheylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[benzylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]pentanedicic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)butyhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(benzylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-(phosphono)oxy]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[cyclohexylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylpropylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylbutylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]oxy]-2-phenylethanoicacid; 2-[[(1-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)hydroxyphosphinyl]oxy]-2-phenyiethanoic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylprop-2-enylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[(methylhydroxyphosphinyl)oxy]hexanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]hexanedioic acid;2-[(methylhydroxyphosphinyl)oxy]heptanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]heptanedioic acid;2-[(methylhydroxyphosphinyl)oxy]octanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]octanedioic acid;2-[(methylhydroxyphosphinyl)oxy]nonanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]nonanedioic acid;2-[(methylhydroxyphosphinyl)oxy]decanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]decanedioic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-cyclohexylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(cyclohexyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-benzylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylpropylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylbutylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2,3,4-trimethoxyphenyl)ethanoicacid; 2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylprop-2-enylethanoic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-thienyl)mrethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid; 2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)methylethanoicacid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)ethylethanoicacid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy)-2-(4-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)propylethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 16. Themethod of claim 14 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[(benzylhydroxyphosphinyl)oxy]pentanedioic acid;2-[(phenylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(butylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(methylhydroxyphosphinyl)oxy]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(phosphono)oxy]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 17. Themethod of claim 10 wherein R₁ and R₂ are straight or branched aliphaticgroups or carbocyclic groups and X is NR₁.
 18. The method of claim 17wherein the NAALADase inhibitor is selected from the group consistingof: 2-[[methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylhydroxyphosphinyl]amino]pentanedioic acid;2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]-2-pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(phosphono)amino]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[cyclchexylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylpropylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylbutylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(1-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylprop-2-enylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-cyclohexylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(cyclohexyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-benzylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylpropylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylbutylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2,3,4-trimethoxyphenyl)ethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenolprop-2-enylethanoic acid;2-[(methylhydroxyphosphinyl)amino]hexanedioic acid;2-[(benzylhydroxyphosphinyl)amino]hexanedioic acid;2-[(methylhydroxyphosphinyl)amino]heptanedioic acid;2-[(benzylhydroxyphosphinyl)amino]heptanedioic acid;2-[(methylhydroxyphosphinyl)amino]octanedioic acid;2-[(benzylhydroxyphosphinyl)amino]octanedioic acid;2-[(methylhydroxyphosphinyl)amino]nonanedioic acid;2-[(benzylhydroxyphosphinyl)amino]nonanedioic acid;2-[(methylhydroxyphosphinyl)amino]decanedioic acid;2-[(benzylhydroxyphosphinyl)amino]decanedioic acid;3-[[(2-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(4-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-pyridyl)propylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(2-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(4-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-indolyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-indolyl)propylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(2-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(4-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-thienyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-thienyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(2-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(4-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(2-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(4-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)propylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)methylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)ethylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)methylethanoicacid; 2-[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)methylethanoicacid; 2-[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)propylethanoic acid; anda pharmaceutically acceptable salt, hydrate, or a mixture thereof. 19.The method of claim 17 wherein the NAALADase inhibitor is selected fromthe group consisting of: 2-[(benzylhydroxyphosphinyl)amino]pentanedioicacid; 2-[(phenylhydroxyphosphinyl)amino]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(butylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(methylhydroxyphosphinyl)amino]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(phosphono)amino]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 20. Themethod of claim 10 wherein R₁ or R₂ is heterocyclic and X is CH₂. 21.The method of claim 20 wherein the NAALADase inhibitor is selected fromthe group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;3-[(2-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(tetrahydrofuranyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-thienyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-thienyl)propanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 22. Themethod of claim 10 wherein R₁ or R₂ is heterocyclic and X is oxygen. 23.The method of claim 22 wherein the NAALADase inhibitor is selected fromthe group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[tetrahydrofuranyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethanoic acid;2-[]benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)ethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 24. Themethod of claim 10 wherein R₁ or R₂ is heterocyclic and X is NR₁. 25.The method of claim 24 wherein the NAALADase inhibitor is a compoundselected from the group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(tetrahydrofuraryl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)ethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 26. Amethod of inhibiting tumor cell growth in an animal which comprises:administering to an animal suffering from a tumor cell growth aneffective amount of a NAALADase inhibitor.
 27. The method of claim 26where the tumor is prostate adenocarcinoma.
 28. The method of claim 26wherein the NAALADase inhibitor is selected from the group consistingof: a glutamate-derived hydroxyphosphinyl derivative compound; an acidicpeptide analog; a conformationally restricted glutamate mimic; andmixtures thereof.
 29. The method of claim 28 wherein the acidic peptideanalog is selected from the group consisting of: Asp-Glu, Glu-Glu,Gly-Glu, gamma-Glu-Glu, and Glu-Glu-Glu.
 30. The method of claim 28wherein the conformationally restricted glutamate mimic is selected fromthe group consisting of: beta:NAAG and quisqualic acid.
 31. The methodof claim 28 wherein the NAALADase inhibitor is a glutamate-derivedhydroxyphosphinyl derivative compound.
 32. The method of claim 26wherein the NAALADase inhibitor is administered in combination with anadditional therapeutic agent selected from the group consisting of:therapeutic hormones, chemotherapeutic hormones, anti-angiogenesisagents, radiolabelled compounds, and mixtures thereof.
 33. The method ofclaim 26 wherein the tumor is selected from the group consisting of:ACTH-producing tumor, acute lymphocytic leukemia, acute nonlymphocyticleukemia, cancer of the adrenal cortex, bladder cancer, brain cancer,breast cancer, cervical cancer, chronic lymphocytic leukemia, chronicmyelocytic leukemia, colorectal cancer, cutaneous T-cell lymphoma,endometrial cancer, esophageal cancer, Ewing's sarcoma, gallbladdercancer, hairy cell leukemia, head & neck cancer, Hodgkin's lymphoma,Kaposi's sarcoma, kidney cancer, liver cancer, lung cancer, lung cancer(small and/or non-small cell), malignant peritoneal effusion, malignantpleural effusion, melanoma, mesothelioma, multiple myeloma,neuroblastoma, non-Hodgkin's lymphoma, osteosarcoma, ovary cancer, ovary(germ cell) cancer, pancreatic cancer, penis cancer, prostateadenocarcinoma, retinoblastoma, skin cancer, soft tissue sarcoma,squamous cell carcinomas, stomach cancer, testicular cancer, thyroidcancer, trophoblastic neoplasms, cancer of the uterus, vaginal cancer,cancer of the vulva, and Wilm's tumor.
 34. The method of claim 26wherein the tumor is prostatic adenocarcinoma.
 35. The method of claim26 wherein the tumor is selected from the group consisting of: braincancer, cancer of the adrenal cortex, kidney cancer, and testicularcancer.
 36. The method of claim 26 wherein the NAALADase inhibitorcomprises a compound having the following formula:

wherein R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; X is CH₂, O, or NR₁, where R₁ is defined above;and R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid, wherein said alkyl,alkenyl, cycloalkyl, cycloalkenyl or aryl groups may be optionallysubstituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₁-C₇cycloalkenyl, C₁-C₄ alkyl, C₁-C₄ alkenyl, halo, hydroxy, carboxy, nitro,trifluoromethyl, C₁-C₆ straight or branched chain alkyl or alkenyl,C₁-C₄ alkoxy, C₁-C₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar₁, andwhere Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl,tetrahydrofuranyl, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-, or4-pyridyl, or phenyl, having one to five substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxy, carboxy, nitro, trifluoromethyl, C₁-C₆ straight or branchedalkyl or alkenyl, C₁-C₄ alkoxy , C₁-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; or pharmaceutically acceptable salts, hydrates, or mixturesthereof.
 37. The method of claim 36 wherein R₁ and R₂ are straight orbranched aliphatic groups or carbocyclic groups and X is CH₂.
 38. Themethod of claim 37 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[[methylhydroxyphosphinyl]methyl]pentanedioicacid; 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[benzylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-(phosphonomethyl)pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;3-(methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(cyclohexylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((cyclohexyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylpropylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylbutylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylprop-2-enylhydroxyphosphinyl)-2-phenylpropanoic acid;2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid;2-[(methylhydroxyphosphinyl)methyl]hexanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]hexanedioic acid;2-[(methylhydroxyphosphinyl)methyl]heptanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]heptanedioic acid;2-[(methylhydroxyphosphinyl)methyl]octanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]octanedioic acid;2-[(methylhydroxyphosphinyl)methyl]nonanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]nonanedioic acid;2-[(methylhydroxyphosphinyl)methyl]decanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]decanedioic acid;3-(benzylhydroxyphosphinyl)-2-methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-cyclohexylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(cyclohexyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-benzylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylbutylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2,3,4-trimethoxyphenyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylprop-2-phenylpropanoic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;3-[[(2-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(4-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-pyridyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-pyridyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(2-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(4-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-indolyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-indolyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(2-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(4-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[[(3-thienyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propylpropanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 39. Themethod of claim 37 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[(benzylhydroxyphosphinyl)methyl]pentanedioicacid; 2-[(phenylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-(phosphonomethyl)pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 40. Themethod of claim 36 wherein R₁ and R₂ are straight or branched orcarbocyclic groups and X is oxygen.
 41. The method of claim 40 whereinthe NAALADase inhibitor is selected from the group consisting of:2-[[methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[butylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[benzylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl))butylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[benzylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(phosphono)oxy]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[cyclohexylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylpropylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylbutylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]oxy]-2-phenylethanoicacid; 2-[[(1-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl)]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylprop-2-enylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[(methylhydroxyphosphinyl)oxy]hexanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]hexanedioic acid;2-[(methylhydroxyphosphinyl)oxy]heptanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]heptanedioic acid;2-[(methylhydroxyphosphinyl)oxy]octanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]octanedioic acid;2-[(methylhydroxyphosphinyl)oxy]nonanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]nonanedioic acid;2-[(methylhydroxyphosphinyl)oxy]decanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]decanedioic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-cyclohexylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(cyclohexyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-benzylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylpropylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylbutylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2,3,4-trimethoxyphenyl)ethanoicacid; 2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylprop-2-enylethanoic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid; 2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)methylethanoicacid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)ethylethanoicacid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl3oxy]-2-(3-thienyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)propylethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 42. Themethod of claim 40 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[(benzylhydroxyphosphinyl)oxy]pentanedioic acid;2-[(phenylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(butylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(methylhydroxyphosphinyl)oxy]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(phosphono)oxy]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 43. Themethod of claim 36 wherein R₁ and R₂ are straight or branched orcarbocyclic and X is NR₁.
 44. The method of claim 43 wherein theNAALADase inhibitor is selected from the group consisting of:2-[[methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylhydroxyphosphinyl]amino]pentanedioic acid;2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid; 2-[[(23,4-trimethoxyphenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-([(2-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(phosphono)amino]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[cyclohexylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylpropylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylbutylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(1-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl)]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl}propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylprop-2-enylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-cyclohexylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(cyclohexyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-benzylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylpropylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylbutylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2,3,4-trimethoxyphenyl)ethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)ethylethanoic acid;2-[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenolprop-2-enylethanoic acid;2-[(methylhydroxyphosphinyl)amino]hexanedioic acid;2-[(benzylhydroxyphosphinyl)amino]hexanedioic acid;2-[(methylhydroxyphosphinyl)amino]heptanedioic acid;2-[(benzylhydroxyphosphinyl)amino]heptanedioic acid;2-[(methylhydroxyphosphinyl)amino]octanedioic acid;2-[(benzylhydroxyphosphinyl)amino]octanedioic acid;2-[(methylhydroxyphosphinyl)amino]nonanedioic acid;2-[(benzylhydroxyphosphinyl)amino]nonanedioic acid;2-[(methylhydroxyphosphinyl)amino]decanedioic acid;2-[(benzylhydroxyphosphinyl)amino]decanedioic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(2-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(4-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(2-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(4-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)propylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)methylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)ethylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)propylethanoicacid; and a pharmaceutically acceptable salt, hydrate, or a mixturethereof.
 45. The method of claim 43 wherein the NAALADase inhibitor isselected from the group consisting of:2-[(benzylhydroxyphosphinyl)amino]pentanedioic acid;2-[(phenylhydroxyphosphinyl)amino]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(butylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(methylhydroxyphosphinyl)amino]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(phosphono)amino]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 46. Themethod of claim 36 wherein R₁ or R₂ is heterocyclic and X is CH₂. 47.The method of claim 46 wherein the NAALADase inhibitor is selected fromthe group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;3-[(2-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(tetrahydrofuranyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl2-(2-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-thienyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-thienyl)propanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 48. Themethod of claim 36 wherein R₁ or R₂ is heterocyclic and X is oxygen. 49.The method of claim 48 wherein the NAALADase inhibitor is selected fromthe group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)ethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 50. Themethod of claim 36 wherein R₁ or R₂ is heterocyclic and X is NR₁. 51.The method of claim 50 wherein the NAALADase inhibitor is a compoundselected from the group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)ethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 52. Amethod of inhibiting NAALADase enzyme activity in an animal whichcomprises: administering to an animal suffering from a disorder relatedto NAALADase enzyme activity an effective amount of a NAALADaseinhibitor.
 53. The method of claim 52 wherein the NAALADase inhibitor isselected from the group consisting of: a glutamate-derivedhydroxyphosphinyl derivative compound; an acidic peptide analog; aconformationally restricted glutamate mimic; and mixtures thereof. 54.The method of claim 53 wherein the acidic peptide analog is selectedfrom the group consisting of: Asp-Glu, Glu-Glu, Gly-Glu, gamma-Glu-Glu,and Glu-Glu-Glu.
 55. The method of claim 53 wherein the conformationallyrestricted glutamate mimic is selected from the group consisting of:beta:NAAG and quisqualic acid.
 56. The method of claim 53 wherein theNAALADase inhibitor is a glutamate-derived hydroxyphosphinyl derivativecompound.
 57. The method of claim 52 wherein the NAALADase inhibitor isadministered in combination with an additional therapeutic agentselected from the group consisting of: therapeutic hormones,chemotherapeutic hormones, anti-angiogenesis agents, radiolabelledcompounds, and mixtures thereof.
 58. The method of claim 52 wherein thedisorder related to NAALADase enzyme activity is prostate diseasewherein the prostate disease is selected from the group consisting ofprostate cancer and benign prostatic hyperplasia.
 59. The method ofclaim 52 wherein the NAALADase inhibitor comprises a compound having thefollowing formula:

wherein R₁ is hydrogen, C₁-C₉ straight or branched chain alkyl, C₂-C₉straight or branched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; X is CH₂, O, or NR₁, where R₁ is defined above;and R₂ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl group, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, orAr₁, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or aryl groupmay be optionally substituted with carboxylic acid, wherein said alkyl,alkenyl, cycloalkyl, cycloalkenyl or aryl groups may be optionallysubstituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇cycloalkenyl, C₁-C₄ alkyl, C₁-C₄ alkenyl, halo, hydroxy, carboxy, nitro,trifluoromethyl, C₁-C₆ straight or branched chain alkyl or alkenyl,C₁-C₄ alkoxy, C₁-C₄ alkenyloxy, phenoxy, benzyloxy, amino, or Ar₁, andwhere Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 4-indolyl, 2-furyl, 3-furyl,tetrahydrofuranyl, 2-thienyl, 3-thienyl, 4-thienyl, 2-, 3-, or4-pyridyl, or phenyl, having one to five substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxy, carboxy, nitro, trifluoromethyl, C₁-C₆ straight or branchedalkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; or pharmaceutically acceptable salts, hydrates, or mixturesthereof.
 60. The method of claim 59 wherein R₁ and R₂ are straight orbranched aliphatic groups or carbocyclic groups and X is CH₂.
 61. Themethod of claim 60 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[[methylhydroxyphosphinyl]methyl]pentanedioicacid; 2-[[ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[benzylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-(phosphonomethyl)pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;3-(methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(cyclohexylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((cyclohexyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylpropylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylbutylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)hydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)methylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)ethylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)propylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((1-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-((2-naphthyl)butylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(phenylprop-2-enylhydroxyphosphinyl)-2-phenylpropanoic acid;2-[(benzylhydroxyphosphinyl)methyl]pentanedioic acid;2-[(methylhydroxyphosphinyl)methyl]hexanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]hexanedioic acid;2-[(methylhydroxyphosphinyl)methyl]heptanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]heptanedioic acid;2-[(methylhydroxyphosphinyl)methyl]octanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]octanedioic acid;2-[(methylhydroxyphosphinyl)methyl]nonanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]nonanedioic acid;2-[(methylhydrcxyphosphinyl)methyl]decanedioic acid;2-[(benzylhydroxyphosphinyl)methyl]decanedioic acid;3-(benzylhydroxyphosphinyl)-2-methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-cyclohexylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(cyclohexyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-benzylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylpropylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylbutylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2,3,4-trimethoxyphenyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(1-naphthyl)butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-naphthyl)butylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-phenylprop-2-enyl propanoic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]methyl]pentanedioic acid;3-[(2-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-pyridyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(tetrahydrofuranyl)methylhydroxyphosphinyl]2-phenylpropanoic acid;3-[(tetrahydrofuranyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(tetrahydrofuranyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-indolyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-thienyl)methylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)ethylhydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)propylhydroxyphosphinyl]-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-indolyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-thienyl)methylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)ethylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propylpropanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 62. Themethod of claim 60 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[(benzylhydroxyphosphinyl)methyl]pentanedioicacid; 2-[(phenylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)methyl]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-(phosphonomethyl)pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]methyl]pentanedioic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 63. Themethod of claim 59 wherein R₁ and R₂ are straight or branched aliphaticgroups or carbocyclic groups and X is oxygen.
 64. The method of claim 63wherein the NAALADase inhibitor is selected from the group consistingof: 2-[[methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[butylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[benzylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[benzylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(phosphono)oxy]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[cyclohexylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylpropylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylbutylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]oxy]-2-phenylethanoicacid; 2-[[(2-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-naphthyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl)]oxy]-2-phenylethanoic acid;2-[[(3-naphthyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-naphthyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-naphthyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-naphthyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-naphthyl)butylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[phenylprop-2-enylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[(methylhydroxyphosphinyl)oxy]hexanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]hexanedioic acid;2-[(methylhydroxyphosphinyl)oxy]heptanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]heptanedioic acid;2-[(methylhydroxyphosphinyl)oxy]octanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]octanedioic acid;2-[(methylhydroxyphosphinyl)oxy]nonanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]nonanedioic acid;2-[(methylhydroxyphosphinyl)oxy]decanedioic acid;2-[(benzylhydroxyphosphinyl)oxy]decanedioic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(cyclohexyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-benzylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylpropylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylbutylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2,3,4-trimethoxyphenyl)ethanoicacid; 2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(1-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-phenylprop-2-enylethanoic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoicacid; 2-[[(2-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-indolyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)propylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-thienyl)methylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)ethylhydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)propylhydroxyphosphinyl]oxy]2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)methylethanoic acid;2-[[(benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)methylethanoicacid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)ethylethanoicacid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrafuranyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)propylethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 65. Themethod of claim 63 wherein the NAALADase inhibitor is selected from thegroup consisting of: 2-[(benzylhydroxyphosphinyl)oxy]pentanedioic acid;2-[(phenylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(butylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(methylhydroxyphosphinyl)oxy]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)oxy]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[(phosphono)oxy]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]oxy]pentanedioic acid;and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.66. The method of claim 59 wherein R_(1 and R) ₂ are straight orbranched aliphatic groups or carbocyclic and X is NR₁.
 67. The method ofclaim 66 wherein the NAALADase inhibitor is selected from the groupconsisting of: 2-[[methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[cyclohexylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylhydroxyphosphinyl]amino]pentanedioic acid;2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylpropylhydroxyphosphinyl]amino]pentanedioic acid;2-[[phenylbutylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2,3,4-trimethoxyphenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(phenylprop-2-enyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[benzylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(phosphono)amino]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[cyclohexylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(cyclohexyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylpropylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylbutylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2,3,4-trimethoxyphenyl)-3-hydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(1-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)methylhydroxyphosphinyl)]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl}propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(1-naphthyl)butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-naphthyl)butylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[phenylprop-2-enylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-cyclohexylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(cyclohexyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-benzylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylpropylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenylbutylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2,3,4-trimethoxyphenyl)ethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)methylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)ethylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)propylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(1-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-naphthyl)butylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-phenolprop-2-enylethanoic acid;2-[(methylhydroxyphosphinyl)amino]hexanedioic acid;2-[(benzylhydroxyphosphinyl)amino]hexanedioic acid;2-[(methylhydroxyphosphinyl)amino]heptanedioic acid;2-[(benzylhydroxyphosphinyl)amino]heptanedioic acid;2-[(methylhydroxyphosphinyl)amino]octanedioic acid;2-[(benzylhydroxyphosphinyl)amino]octanedioic acid;2-[(methylhydroxyphosphinyl)amino]nonanedioic acid;2-[(benzylhydroxyphosphinyl)amino]nonanedioic acid;2-[(methylhydroxyphosphinyl)amino]decanedioic acid;2-[(benzylhydroxyphosphinyl)amino]decanedioic acid;3-[[(2-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(4-pyridyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-pyridyl)propylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(2-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(4-indolyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-indolyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-indolyl)propylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(2-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-thienyl)methylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(4-thienyl)methylhydroxyphosphinyl amino]pentanedioic acid;3-[[(3-thienyl)ethylhydroxyphosphinyl]amino]pentanedioic acid;3-[[(3-thienyl)propylhydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-pyridyl)methylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)propylhydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid;2-[[(tetrahydrofuranyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(2-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(4-indolyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-indolyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(2-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(4-thienyl)methylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)ethylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[(3-thienyl)propylhydroxyphosphinyl]amino]-2-phenylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)propylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)methylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)ethylethanoicacid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrafuranyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)propylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)methylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethylethanoicacid; 2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)propylethanoicacid; and a pharmaceutically acceptable salt, hydrate, or a mixturethereof.
 68. The method of claim 66 wherein the NAALADase inhibitor isselected from the group consisting of:2-[(benzylhydroxyphosphinyl)amino]pentanedioic acid;2-[(phenylhydroxyphosphinyl)amino]pentanedioic acid;2-[[((hydroxy)phenylmethyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(butylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(3-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(3-phenylpropylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(4-fluorophenyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(methylhydroxyphosphinyl)amino]pentanedioic acid;2-[(phenylethylhydroxyphosphinyl)amino]pentanedioic acid;2-[[(4-methylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-methoxybenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-fluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(pentafluorobenzyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[(phosphono)amino]pentanedioic acid;2-[[(3-trifluoromethylbenzyl)hydroxyphosphinyl]amino]pentanedioic acid;and a pharmaceutically acceptable salt, hydrate, or a mixture thereof.69. The method of claim 59 wherein R₁ or R₂ is heterocyclic and X isCH₂.
 70. The method of claim 69 wherein the NAALADase inhibitor isselected from the group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]methyl]pentanedioic acid;3-[(2-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-pyridyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(tetrahydrofuranyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-indolyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(2-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(3-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-[(4-thienyl)hydroxyphosphinyl]-2-phenylpropanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-pyridyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(tetrahydrofuranyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-indolyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(2-thienyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(3-thienyl)propanoic acid;3-(benzylhydroxyphosphinyl)-2-(4-thienyl)propanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 71. Themethod of claim 69 wherein R₁ or R₂ is heterocyclic and X is oxygen. 72.The method of claim 71 wherein the NAALADase inhibitor is selected fromthe group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]oxy]pentanedioic acid;2-[[(2-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-pyridyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-indolyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(2-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(3-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[(4-thienyl)hydroxyphosphinyl]oxy]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(tetrahydrofuranyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(2-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(3-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]oxy]-2-(4-thienyl)ethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.
 73. Themethod of claim 59 wherein R₁ or R₂ is heterocyclic and X is NR₁. 74.The method of claim 73 wherein the NAALADase inhibitor is a compoundselected from the group consisting of:2-[[(2-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-pyridyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-indolyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(3-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(4-thienyl)hydroxyphosphinyl]amino]pentanedioic acid;2-[[(2-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-pyridyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(tetrahydrofuranyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-indolyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(2-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(3-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[(4-thienyl)hydroxyphosphinyl]amino]-2-phenylethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-pyridyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(tetrahydrofuranyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-indolyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(2-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(3-thienyl)ethanoic acid;2-[[benzylhydroxyphosphinyl]amino]-2-(4-thienyl)ethanoic acid; and apharmaceutically acceptable salt, hydrate, or a mixture thereof.